1
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Xiong S, Zhang S, Yue N, Cao J, Wu C. CAR-T cell therapy in the treatment of relapsed or refractory primary central nervous system lymphoma: recent advances and challenges. Leuk Lymphoma 2025; 66:1045-1057. [PMID: 39898872 DOI: 10.1080/10428194.2025.2458214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 01/01/2025] [Accepted: 01/20/2025] [Indexed: 02/04/2025]
Abstract
Primary central nervous system lymphoma (PCNSL) is a rare and aggressive lymphoma that is isolated in the central nervous system (CNS) or vitreoretinal space. High-dose methotrexate (HD-MTX)-based immunochemotherapy is the frontline for its treatment, with a high early response rate. However, relapsed or refractory (R/R) patients present numerous difficulties and challenges in clinical treatment. Chimeric antigen receptor (CAR)-T cells offer a promising option for the treatment of hematologic malignancies, especially in the R/R B-cell lymphoma and multiple myeloma. Despite the exclusion of most PCNSL cases from pivotal CAR-T cell trials due to their specific tumor microenvironment (TME), available preclinical and clinical studies with small cohorts suggest an overall acceptable safety profile and remarkable anti-tumor effects. In this review, we will provide the development process of CAR-T cells and summarize the research progress, limitations, and future perspectives of CAR-T cell therapy in patients with R/R PCNSL.
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MESH Headings
- Humans
- Immunotherapy, Adoptive/methods
- Immunotherapy, Adoptive/adverse effects
- Central Nervous System Neoplasms/therapy
- Central Nervous System Neoplasms/pathology
- Central Nervous System Neoplasms/immunology
- Receptors, Chimeric Antigen/metabolism
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/genetics
- Tumor Microenvironment/immunology
- Neoplasm Recurrence, Local/therapy
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/immunology
- Drug Resistance, Neoplasm
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Treatment Outcome
- Lymphoma/therapy
- Lymphoma/pathology
- Lymphoma/immunology
- Animals
- Clinical Trials as Topic
- Receptors, Antigen, T-Cell
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Affiliation(s)
- Shuzhen Xiong
- Department of Hematology, Lanzhou University Second Hospital, Lanzhou, China
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2
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Hushmandi K, Imani Fooladi AA, Reiter RJ, Farahani N, Liang L, Aref AR, Nabavi N, Alimohammadi M, Liu L, Sethi G. Next-generation immunotherapeutic approaches for blood cancers: Exploring the efficacy of CAR-T and cancer vaccines. Exp Hematol Oncol 2025; 14:75. [PMID: 40382583 DOI: 10.1186/s40164-025-00662-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 04/25/2025] [Indexed: 05/20/2025] Open
Abstract
Recent advancements in immunotherapy, particularly Chimeric antigen receptor (CAR)-T cell therapy and cancer vaccines, have significantly transformed the treatment landscape for leukemia. CAR-T cell therapy, initially promising in hematologic cancers, faces notable obstacles in solid tumors due to the complex and immunosuppressive tumor microenvironment. Challenges include the heterogeneous immune profiles of tumors, variability in antigen expression, difficulties in therapeutic delivery, T cell exhaustion, and reduced cytotoxic activity at the tumor site. Additionally, the physical barriers within tumors and the immunological camouflage used by cancer cells further complicate treatment efficacy. To overcome these hurdles, ongoing research explores the synergistic potential of combining CAR-T cell therapy with cancer vaccines and other therapeutic strategies such as checkpoint inhibitors and cytokine therapy. This review describes the various immunotherapeutic approaches targeting leukemia, emphasizing the roles and interplay of cancer vaccines and CAR-T cell therapy. In addition, by discussing how these therapies individually and collectively contribute to tumor regression, this article aims to highlight innovative treatment paradigms that could enhance clinical outcomes for leukemia patients. This integrative approach promises to pave the way for more effective and durable treatment strategies in the oncology field. These combined immunotherapeutic strategies hold great promise for achieving more complete and lasting remissions in leukemia patients. Future research should prioritize optimizing treatment sequencing, personalizing therapeutic combinations based on individual patient and tumor characteristics, and developing novel strategies to enhance T cell persistence and function within the tumor microenvironment. Ultimately, these efforts will advance the development of more effective and less toxic immunotherapeutic interventions, offering new hope for patients battling this challenging disease.
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Affiliation(s)
- Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Islamic Republic of Iran.
| | - Abbas Ali Imani Fooladi
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, 78229, USA
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Liping Liang
- Guangzhou Key Laboratory of Digestive Diseases, Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | | | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Le Liu
- Integrated Clinical Microecology Center, Shenzhen Hospital, Southern Medical University, Shenzhen, 518000, China.
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
| | - Gautam Sethi
- Department of Pharmacology and NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
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3
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Kim H, Lee M, Han B, Kim J, Cho D, Doh J, Chung AJ. Advancing Allogeneic NK Cell Immunotherapy through Microfluidic Gene Delivery. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412544. [PMID: 40052491 PMCID: PMC12061328 DOI: 10.1002/advs.202412544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 01/26/2025] [Indexed: 05/10/2025]
Abstract
Chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer treatment, yet challenges such as manufacturing complexity, high costs, and safety concerns have spurred the development of alternatives like CAR-natural killer (NK) cell immunotherapies. CAR-NK cell therapies provide innate cytotoxicity with antigen-independent targeting, reducing safety risks while improving therapeutic efficacy. However, efficient genomic engineering and large-scale production of allogeneic NK cells remain significant obstacles. To address these challenges, a novel microfluidic gene delivery platform is developed, the Y-hydroporator, designed for allogeneic NK cell immunotherapy. This platform features a Y-shaped microchannel where NK cells experience rapid hydrodynamic stretching near the stagnation point, creating transient membrane discontinuities that facilitate the uptake of exogenous cargo. The Y-hydroporator achieves high delivery and transfection efficiency, processing ≈2 × 106 cells min-1 while maintaining long-term cell viability (>89%) and functionality. Using this platform, human primary CAR-NK cells and NKG2A-knockout NK cells are successfully generated by delivering anti-CD19 CAR mRNA and CRISPR/Cas9 ribonucleoproteins, respectively. These engineered NK cells demonstrated enhanced cytotoxicity, underscoring the potential of the Y-hydroporator as a transformative tool for advancing allogeneic NK cell-based immunotherapies.
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Affiliation(s)
- Hyelee Kim
- Department of BioengineeringKorea UniversitySeoul02841Republic of Korea
- Interdisciplinary Program in Precision Public Health (PPH)Korea UniversitySeoul02841Republic of Korea
| | - Mujin Lee
- Department of Materials Science and EngineeringSeoul National UniversitySeoul08826Republic of Korea
| | - Bohwa Han
- Department of Materials Science and EngineeringSeoul National UniversitySeoul08826Republic of Korea
| | - Jinho Kim
- Department of Health Sciences and TechnologySAIHSTSungkyunkwan UniversitySeoul06355Republic of Korea
| | - Duck Cho
- Department of Health Sciences and TechnologySAIHSTSungkyunkwan UniversitySeoul06355Republic of Korea
- Department of Laboratory Medicine and GeneticsSamsung Medical CenterSungkyunkwan University School of MedicineSeoul03063Republic of Korea
| | - Junsang Doh
- Department of Materials Science and EngineeringSeoul National UniversitySeoul08826Republic of Korea
| | - Aram J. Chung
- Department of BioengineeringKorea UniversitySeoul02841Republic of Korea
- Interdisciplinary Program in Precision Public Health (PPH)Korea UniversitySeoul02841Republic of Korea
- School of Biomedical EngineeringKorea UniversitySeoul02841Republic of Korea
- MxT BiotechSeoul04785Republic of Korea
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4
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Werner J, Lee AG, Zhang C, Abelson S, Xirenayi S, Rivera J, Yousuf K, Shin H, Patiño-Escobar B, Bachl S, Mandal K, Barpanda A, Ramos E, Izgutdina A, Chaudhuri S, Temple WC, Bhatnagar S, Dardis JK, Meyer J, Morales C, Meshinchi S, Loh ML, Braun B, Tasian SK, Wiita AP, Stieglitz E. Cellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia. Nat Commun 2025; 16:3804. [PMID: 40268927 PMCID: PMC12019388 DOI: 10.1038/s41467-025-59040-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 04/07/2025] [Indexed: 04/25/2025] Open
Abstract
Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder that predominantly affects infants and young children. Hematopoietic stem cell transplantation (HSCT) is standard of care, but post-HSCT relapse is common, highlighting the need for innovative therapies. While adoptive immunotherapy with chimeric antigen receptor (CAR) T cells has improved outcomes for patients with advanced lymphoid malignancies, it has not been comprehensively evaluated in JMML. In the present study, we use bulk and single-cell RNA sequencing, mass spectrometry, and flow cytometry to identify overexpression of CLL-1 (encoded by CLEC12A) on the cell surface of cells from patients with JMML. We develop immunotherapy with CLL-1 CAR T cells (CLL1CART) for preclinical testing and report in vitro and in vivo anti-leukemia activity. Notably, CLL1CART reduce the number of leukemic stem cells and serial transplantability in vivo. These preclinical data support the development and clinical investigation of CLL-1-targeting immunotherapy in children with relapsed/refractory JMML.
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MESH Headings
- Humans
- Leukemia, Myelomonocytic, Juvenile/therapy
- Leukemia, Myelomonocytic, Juvenile/immunology
- Leukemia, Myelomonocytic, Juvenile/genetics
- Leukemia, Myelomonocytic, Juvenile/pathology
- Animals
- Mice
- Immunotherapy, Adoptive/methods
- Lectins, C-Type/genetics
- Lectins, C-Type/immunology
- Lectins, C-Type/metabolism
- Receptors, Mitogen/genetics
- Receptors, Mitogen/immunology
- Receptors, Mitogen/metabolism
- Female
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/genetics
- Male
- Xenograft Model Antitumor Assays
- Child
- Mice, SCID
- Neoplastic Stem Cells/immunology
- Infant
- T-Lymphocytes/immunology
- T-Lymphocytes/transplantation
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Affiliation(s)
- Juwita Werner
- Department of Pediatrics, Benioff Children's Hospitals, University of California, San Francisco, CA, USA
- Department of Pediatric Hematology and Oncology and Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - Alex G Lee
- Department of Pediatrics, Benioff Children's Hospitals, University of California, San Francisco, CA, USA
| | - Chujing Zhang
- Department of Pediatrics, Benioff Children's Hospitals, University of California, San Francisco, CA, USA
| | - Sydney Abelson
- Department of Pediatrics, Benioff Children's Hospitals, University of California, San Francisco, CA, USA
| | - Sherin Xirenayi
- Department of Pediatrics, Benioff Children's Hospitals, University of California, San Francisco, CA, USA
| | - Jose Rivera
- Department of Pediatrics, Benioff Children's Hospitals, University of California, San Francisco, CA, USA
| | - Khadija Yousuf
- Department of Pediatrics, Benioff Children's Hospitals, University of California, San Francisco, CA, USA
| | - Hanna Shin
- Department of Pediatrics, Benioff Children's Hospitals, University of California, San Francisco, CA, USA
| | | | - Stefanie Bachl
- Department of Medicine, University of California, San Francisco, CA, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
| | - Kamal Mandal
- Department of Laboratory Medicine, University of California, San Francisco, CA, USA
- Department of Animal Biotechnology, Gujarat Biotechnology University, Gandhinagar, India
| | - Abhilash Barpanda
- Department of Laboratory Medicine, University of California, San Francisco, CA, USA
| | - Emilio Ramos
- Department of Laboratory Medicine, University of California, San Francisco, CA, USA
| | - Adila Izgutdina
- Department of Laboratory Medicine, University of California, San Francisco, CA, USA
| | - Sibapriya Chaudhuri
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA
| | - William C Temple
- Division of Pediatric Allergy, Immunology, and Bone Marrow Transplant, University of California, San Francisco, CA, USA
- Division of Pediatric Oncology, University of California, San Francisco, CA, USA
| | - Shubhmita Bhatnagar
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Jackson K Dardis
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Julia Meyer
- Department of Pediatrics, Benioff Children's Hospitals, University of California, San Francisco, CA, USA
| | - Carolina Morales
- Department of Pediatrics, Benioff Children's Hospitals, University of California, San Francisco, CA, USA
| | - Soheil Meshinchi
- Clinical Research Division, Department of Pediatrics, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Mignon L Loh
- Seattle Children's Hospital, The Ben Towne Center for Childhood Cancer Research, University of Washington, Seattle, WA, USA
| | - Benjamin Braun
- Department of Pediatrics, Benioff Children's Hospitals, University of California, San Francisco, CA, USA
| | - Sarah K Tasian
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics and Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
| | - Arun P Wiita
- Department of Laboratory Medicine, University of California, San Francisco, CA, USA
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
- Chan Zuckerberg Biohub San Francisco, San Francisco, CA, USA
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
| | - Elliot Stieglitz
- Department of Pediatrics, Benioff Children's Hospitals, University of California, San Francisco, CA, USA.
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5
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Lu P, Long J. SOHO State of the Art Updates and Next Questions | CD7 CAR-T Therapy for Treating CD7-Positive Hematological Malignancies: Clinical Advances and Future Directions. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2025:S2152-2650(25)00142-9. [PMID: 40374439 DOI: 10.1016/j.clml.2025.04.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 04/11/2025] [Accepted: 04/13/2025] [Indexed: 05/17/2025]
Abstract
CD7 CAR-T cell therapy has emerged as a promising treatment for relapsed/refractory (R/R) CD7-positive hematological malignancies, offering new hope for patients with limited therapeutic options. This review examines the recent clinical advances, challenges, and future directions of CD7 CAR-T therapy. Clinical trials have demonstrated remarkable efficacy of CD7 chimeric antigen receptor T (CD7 CAR-T) cells in treating T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LBL), and other CD7-positive malignancies, with complete remission (CR) rates of 90-95% in bone marrow (BM) and 50% to 60% in extramedullary disease (EMD). Various engineering strategies, including naturally selected CD7-targeted CAR-T cells, gene editing, protein blockers and universal CAR-T cells, have been developed to overcome challenges such as fratricide. While CD7 CAR-T therapy has shown promising initial responses, durable remissions often depend on consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ongoing research is focused on optimizing CAR designs, improving CAR-T cell persistence, and developing novel combination strategies to enhance long-term outcomes. Safety profiles have been generally manageable, with cytokine release syndrome (CRS) and neurotoxicity being the primary concerns. However, prolonged cytopenias and potential long-term immunodeficiency due to depletion of healthy CD7-positive cells remain areas of active investigation. As CD7 CAR-T therapy continues to evolve, future directions include refining patient selection, exploring dual-targeting approaches, and investigating innovative strategies to integrate CAR-T therapy with allo-HSCT. These advancements aim to improve the efficacy, safety, and accessibility of CD7 CAR-T therapy for patients with CD7-positive hematological malignancies.
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Affiliation(s)
- Peihua Lu
- Hebei Yanda Lu Daopei Hospital, Langfang, China; Beijing Lu Daopei Hospital, Beijing, China; Beijing Lu Daopei Institute of Hematology, Beijing, China.
| | - Jing Long
- Beijing Lu Daopei Institute of Hematology, Beijing, China
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6
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Gao H, Wu H, Ning L, Zhou L, Cao M, Huang W, Xie X, Wu H, Chen X, Chen F, Song J, Deng K, Chen P. Transplantation of the MSLN-deficient Thymus Generates MSLN Epitope Reactive T Cells to Attenuate Tumor Progression. Cancer Sci 2025; 116:871-883. [PMID: 39853704 PMCID: PMC11967271 DOI: 10.1111/cas.16458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 01/07/2025] [Accepted: 01/14/2025] [Indexed: 01/26/2025] Open
Abstract
The development of mesothelin (MSLN) epitope reactive T cells is observed in mice that are immunized with the MSLN vaccine. Engineered T cells expressing MSLN-reactive high-affinity TCR exhibit extraordinary therapeutic effects for invasive pancreatic ductal adenocarcinoma in a mouse model. However, the generation of MSLN-reactive T cells through the introduction of MSLN-deficient thymus and the transplantation of the latter as a cure for cancer treatment have not been tested to date. In the present study, the expression of MSLN was mainly identified in medullary thymic epithelial cells (mTECs) but not in hematopoietic cells, cortical thymic epithelial cells (cTECs), endothelial cells, or fibroblast cells in the thymus. The increasement of activated T cells was observed in MSLN-expressing tumors from MSLN-deficient mice, indicating that MSLN-reactive T cells had developed. Finally, in an AOM-DSS-induced mouse model of colorectal cancer (CRC), transplantation of MSLN-deficient thymus repressed the progression of CRC, accompanied by an increased number of IFNγ-expressing T lymphocytes in the tumors. The data from this study demonstrated that ectopic transplantation of MSLN-deficient thymus induced MSLN-specific antitumor responses to MSLN-expressing tumors, and thus attenuated tumor progression.
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Affiliation(s)
- Hanchao Gao
- Department of Nephrology, Shenzhen Longhua District Central HospitalShenzhen Longhua District Key Laboratory for Diagnosis and Treatment of Chronic Kidney DiseaseShenzhenGuangdongChina
| | - Haiyan Wu
- Department of Traumatic OrthopedicsShenzhen Longhua District Central HospitalShenzhenGuangdongChina
| | - Lvwen Ning
- Department of Medical LaboratoryShenzhen Longhua District Central HospitalShenzhenGuangdongChina
| | - Liying Zhou
- Department of GynaecologyShenzhen Longhua District Central HospitalShenzhenGuangdongChina
| | - Mengtao Cao
- Department of Medical LaboratoryShenzhen Longhua District Central HospitalShenzhenGuangdongChina
| | - Wenting Huang
- Department of Traumatic OrthopedicsShenzhen Longhua District Central HospitalShenzhenGuangdongChina
| | - Xihong Xie
- Department of Traumatic OrthopedicsShenzhen Longhua District Central HospitalShenzhenGuangdongChina
| | - Haidong Wu
- Department of Traumatic OrthopedicsShenzhen Longhua District Central HospitalShenzhenGuangdongChina
| | - Xiehui Chen
- Department of Medical LaboratoryShenzhen Longhua District Central HospitalShenzhenGuangdongChina
| | - Feiqiang Chen
- Department of Traumatic OrthopedicsShenzhen Longhua District Central HospitalShenzhenGuangdongChina
| | - Jinqi Song
- Department of Traumatic OrthopedicsShenzhen Longhua District Central HospitalShenzhenGuangdongChina
| | - Kai Deng
- Department of Traumatic OrthopedicsShenzhen Longhua District Central HospitalShenzhenGuangdongChina
| | - Pengfei Chen
- Department of Traumatic OrthopedicsShenzhen Longhua District Central HospitalShenzhenGuangdongChina
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7
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Sarangi R, Mishra S, Mahapatra S. Cancer Vaccines: A Novel Revolutionized Approach to Cancer Therapy. Indian J Clin Biochem 2025; 40:191-200. [PMID: 40123637 PMCID: PMC11928706 DOI: 10.1007/s12291-024-01201-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 02/19/2024] [Indexed: 03/25/2025]
Abstract
Over the past few decades, there has been significant advancement in the field of tumor immunotherapy. For many years vaccination against infectious diseases have been available. On the other hand very few cancer vaccines have been approved for human use. Ideal Cancer vaccines are biological response modifier work by stimulating both humoral and cellular immunity while overcoming the immunological suppression found in tumor. Two types of cancer vaccine: Prophylactic and therapeutic cancer vaccines are recommended for clinical use of individuals. HPV and HBV vaccines are the two widely used preventive vaccine used for treatment of cervical and hepatocellular carcinoma respectively and are approved by Food and Drug Administration (FDA). In therapeutic vaccine only three are approved: Sipuleucel T-cell vaccine for treatment refractory prostatic cancer, BCG vaccine for early bladder cancer and T-VEC for inoperable melanoma. Active ingredient in all cancer vaccines is an antigen. Antigens used for formulating cancer vaccines along with adjuvants optimizes immunogenicity in it. Heterogeneity within and between cancer types, screening and identifying suitable antigen specific to tumors and selection of vaccine delivery platforms are challenges in the development of vaccines. Adoptive cell therapy, Chimeric antigen receptor T cell therapy are recent breakthrough for cancer treatment.
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Affiliation(s)
- RajLaxmi Sarangi
- Departments of Biochemistry, Kalinga Institute of Medical Sciences (KIMS), Bhubaneswar, Odisha 751024 India
| | - Sanjukta Mishra
- Departments of Biochemistry, Kalinga Institute of Medical Sciences (KIMS), Bhubaneswar, Odisha 751024 India
| | - Srikrushna Mahapatra
- Departments of Biochemistry, Kalinga Institute of Medical Sciences (KIMS), Bhubaneswar, Odisha 751024 India
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8
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Fatemi N, Mirbahari SN, Tierling S, Sanjabi F, Shahrivari S, AmeliMojarad M, Amelimojarad M, Mirzaei Rezaei M, Nobaveh P, Totonchi M, Nazemalhosseini Mojarad E. Emerging Frontiers in Colorectal Cancer Therapy: From Targeted Molecules to Immunomodulatory Breakthroughs and Cell-Based Approaches. Dig Dis Sci 2025; 70:919-942. [PMID: 39869166 PMCID: PMC11919954 DOI: 10.1007/s10620-024-08774-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 11/20/2024] [Indexed: 01/28/2025]
Abstract
Colorectal cancer (CRC) is ranked as the second leading cause of cancer-related deaths globally, necessitating urgent advancements in therapeutic approaches. The emergence of groundbreaking therapies, including chimeric antigen receptor-T (CAR-T) cell therapies, oncolytic viruses, and immune checkpoint inhibitors, marks a transformative era in oncology. These innovative modalities, tailored to individual genetic and molecular profiles, hold the promise of significantly enhancing patient outcomes. This comprehensive review explores the latest clinical trials and advancements, encompassing targeted molecular therapies, immunomodulatory agents, and cell-based therapies. By evaluating the strengths, limitations, and potential synergies of these approaches, this research aims to reshape the treatment landscape and improve clinical outcomes for CRC patients, offering new found hope for those who have exhausted conventional options. The culmination of this work is anticipated to pave the way for transformative clinical trials, ushering in a new era of personalized and effective CRC therapy.
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Affiliation(s)
- Nayeralsadat Fatemi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyedeh Nasim Mirbahari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Developmental Biology, School of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
- Department of Genetics, Reproductive Biomedicine Research Center, ACECR, Royan Institute for Reproductive Biomedicine, Tehran, Iran
| | - Sascha Tierling
- Department of Genetics/Epigenetics, Faculty NT, Life Sciences, Saarland University, Saarbrücken, Germany
| | - Fatemeh Sanjabi
- Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical, Tehran, Iran
| | - Shabnam Shahrivari
- Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical, Tehran, Iran
| | - Mandana AmeliMojarad
- Department of Biology, Faculty of Basic Science, Kharrazi University, Tehran, Iran
| | - Melika Amelimojarad
- Department of Biology, Faculty of Basic Science, Kharrazi University, Tehran, Iran
| | - Meygol Mirzaei Rezaei
- School of Advanced Sciences and Technology, Islamic Azad University, Tehran Medical Branch, Tehran, Iran
| | - Parsa Nobaveh
- School of Advanced Sciences and Technology, Islamic Azad University, Tehran Medical Branch, Tehran, Iran
| | - Mehdi Totonchi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Genetics, Reproductive Biomedicine Research Center, ACECR, Royan Institute for Reproductive Biomedicine, Tehran, Iran
| | - Ehsan Nazemalhosseini Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Yeman St, Chamran Expressway, P.O. Box 19857-17413, Tehran, Iran.
- Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.
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9
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Li D, Lan X, Xu L, Zhou S, Luo H, Zhang X, Yu W, Yang Y, Fang X. Influence of gut microbial metabolites on tumor immunotherapy: mechanisms and potential natural products. Front Immunol 2025; 16:1552010. [PMID: 40066456 PMCID: PMC11891355 DOI: 10.3389/fimmu.2025.1552010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 02/06/2025] [Indexed: 05/13/2025] Open
Abstract
In recent years, tumor immunotherapy has made significant breakthroughs in the treatment of malignant tumors. However, individual differences in efficacy have been observed in clinical practice. There is increasing evidence that gut microbial metabolites influence the efficacy of distal tumor immunotherapy via the gut-liver axis, the gut-brain axis and the gut-breast axis, a process that may involve modulating the expression of immune cells and cytokines in the tumor microenvironment (TME). In this review, we systematically explore the relationship between gut microbial metabolites and tumor immunotherapy, and examine the corresponding natural products and their mechanisms of action. The in-depth exploration of this research area will provide new ideas and strategies to enhance the efficacy of tumor immunotherapy and mitigate adverse effects.
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Affiliation(s)
- Dongyang Li
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Xintian Lan
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Linyi Xu
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Shuo Zhou
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Haoming Luo
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Xiaoying Zhang
- Department of Clinical Pharmacy, The First Hospital of Jilin University, Changchun, China
| | - Wenbo Yu
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Yonggang Yang
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Xiaoxue Fang
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
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10
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Das L, Das S. A comprehensive insights of cancer immunotherapy resistance. Med Oncol 2025; 42:57. [PMID: 39883235 DOI: 10.1007/s12032-025-02605-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Accepted: 01/09/2025] [Indexed: 01/31/2025]
Abstract
Cancer is a major global health issue that is usually treated with multiple therapies, such as chemotherapy and targeted therapies like immunotherapy. Immunotherapy is a new and alternative approach to treating various types of cancer that are difficult to treat with other methods. Although immune checkpoint inhibitors have shown promise for long-term efficacy, they have limited effectiveness in common cancer types such as breast, prostate, and lung. Some patients do not respond to immunotherapy, while others develop resistance to the treatment over time, which is classified as primary or acquired resistance. Cancer immunotherapy, specifically immune checkpoint inhibitor-based resistance involves multiple factors such as genes, metabolism, inflammation, and angiogenesis. However, cutting-edge research has identified the mechanisms of immunotherapy resistance and possible solutions. Current research may improve biomarker identification and modify treatment strategies, which will lead to better clinical outcomes. This review provides a comprehensive discussion of the current mechanisms of immunotherapy resistance, related biomarker modulation, and strategies to overcome resistance.
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Affiliation(s)
- Laavanya Das
- Department of Food and Nutrition, Brainware University, 398, Ramkrishnapur Rd, Barasat, Kolkata, West Bengal, 700125, India
| | - Subhadip Das
- Department of In Vivo Pharmacology, TCG Lifesciences Pvt. Ltd, BN 7, Sector V, Salt Lake City, Kolkata, West Bengal, 700091, India.
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11
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Kong Y, Li J, Zhao X, Wu Y, Chen L. CAR-T cell therapy: developments, challenges and expanded applications from cancer to autoimmunity. Front Immunol 2025; 15:1519671. [PMID: 39850899 PMCID: PMC11754230 DOI: 10.3389/fimmu.2024.1519671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 12/17/2024] [Indexed: 01/25/2025] Open
Abstract
Chimeric Antigen Receptor (CAR)-T cell therapy has rapidly emerged as a groundbreaking approach in cancer treatment, particularly for hematologic malignancies. However, the application of CAR-T cell therapy in solid tumors remains challenging. This review summarized the development of CAR-T technologies, emphasized the challenges and solutions in CAR-T cell therapy for solid tumors. Also, key innovations were discussed including specialized CAR-T, combination therapies and the novel use of CAR-Treg, CAR-NK and CAR-M cells. Besides, CAR-based cell therapy have extended its reach beyond oncology to autoimmune disorders. We reviewed preclinical experiments and clinical trials involving CAR-T, Car-Treg and CAAR-T cell therapies in various autoimmune diseases. By highlighting these cutting-edge developments, this review underscores the transformative potential of CAR technologies in clinical practice.
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Affiliation(s)
| | | | | | - Yanwei Wu
- School of Medicine, Shanghai University, Shanghai, China
| | - Liang Chen
- School of Medicine, Shanghai University, Shanghai, China
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12
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Lee J, Song J, Yoo W, Choi H, Jung D, Choi E, Jo SG, Gong EY, Jeoung YH, Park YS, Son WC, Lee H, Lee H, Kim JJ, Kim T, Lee S, Park JJ, Kim TD, Kim SH. Therapeutic potential of anti-ErbB3 chimeric antigen receptor natural killer cells against breast cancer. Cancer Immunol Immunother 2025; 74:73. [PMID: 39751931 PMCID: PMC11698710 DOI: 10.1007/s00262-024-03923-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 12/13/2024] [Indexed: 01/04/2025]
Abstract
ErbB3 is markedly overexpressed in breast cancer cells and is associated with resistance and metastasis. Additionally, ErbB3 expression levels are positively correlated with low densities of tumor-infiltrating lymphocytes, a marker of poor prognosis. Consequently, ErbB3 is a promising therapeutic target for cancer immunotherapy. Here, we report the generation of ErbB3-targeted chimeric antigen receptor (CAR)-modified natural killer (NK) cells by transducing cord blood-derived primary NK cells using vsv-g envelope-pseudotyped lentiviral vectors. Transduced cells displayed stable CAR-expressing activity and increased cytotoxicity against ErbB3-positive breast cancer cell lines. Furthermore, anti-ErbB3 (aErbB3) CAR-NK cells strongly reduced the tumor burden in the SK-BR-3 xenograft mouse model without observable side effects. These findings underscore the potential of aErbB3 CAR-NK cells as targeted immunotherapy for ErbB3-positive breast cancer, suggesting a promising alternative to conventional treatments.
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Affiliation(s)
- Juheon Lee
- Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea
| | - Jinhoo Song
- Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea
| | - Wonbeak Yoo
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Hyunji Choi
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Dana Jung
- Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea
| | - Eunjeong Choi
- Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea
| | - Seo-Gyeong Jo
- Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea
| | - Eun-Yeung Gong
- Department of Medicinal Biotechnology, College of Health Science, Dong-A University, Busan, 49315, Republic of Korea
| | - Young-Hee Jeoung
- Department of Medicinal Biotechnology, College of Health Science, Dong-A University, Busan, 49315, Republic of Korea
| | - You-Soo Park
- Department of Research Center, Dongnam Institute of Radiological and Medical Sciences Busan, Busan, 46033, Republic of Korea
| | - Woo-Chang Son
- Department of Research Center, Dongnam Institute of Radiological and Medical Sciences Busan, Busan, 46033, Republic of Korea
| | - Hosuk Lee
- ISU Abxis, Drug Discovery Division, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Hayoung Lee
- ISU Abxis, Drug Discovery Division, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Jeom Ji Kim
- ISU Abxis, Drug Discovery Division, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - TaeEun Kim
- ISU Abxis, Drug Discovery Division, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Sooyun Lee
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
| | - Jang-June Park
- ISU Abxis, Drug Discovery Division, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea.
| | - Tae-Don Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea.
| | - Seok-Ho Kim
- Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea.
- Department of Medicinal Biotechnology, College of Health Science, Dong-A University, Busan, 49315, Republic of Korea.
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13
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Agarwal D, Sharma G, Khadwal A, Toor D, Malhotra P. Advances in Vaccines, Checkpoint Blockade, and Chimeric Antigen Receptor-Based Cancer Immunotherapeutics. Crit Rev Immunol 2025; 45:65-80. [PMID: 39612278 DOI: 10.1615/critrevimmunol.2024053025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2024]
Abstract
Increase in cancer cases and research driven by understanding its causes, facilitated development of novel targeted immunotherapeutic strategies to overcome nonspecific cytotoxicity associated with conventional chemotherapy and radiotherapy. These target specific immunotherapeutic regimens have been evaluated for their efficacy, including: (1) vaccines harnessing tumor specific/associated antigens, (2) checkpoint blockade therapy using monoclonal antibodies against PD1, CTLA-4 and others, and (3) adoptive cell transfer approaches viz. chimeric antigen receptor (CAR)-cell-based therapies. Here, we review recent advancements on these target specific translational immunotherapeutic strategies against cancer/s and concerned limitations.
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Affiliation(s)
- Disha Agarwal
- Department of Translational & Regenerative Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | | | - Alka Khadwal
- Department of Clinical Hematology and Medical Oncology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Devinder Toor
- Amity Institute of Virology and Immunology, Amity University Uttar Pradesh, Sector-125, Noida, 201313, Uttar Pradesh, India
| | - Pankaj Malhotra
- Department of Clinical Hematology and Medical Oncology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
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14
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Canciani G, Fabozzi F, Pinacchio C, Ceccarelli M, Del Bufalo F. Developing CAR T-Cell Therapies for Pediatric Solid Tumors. Paediatr Drugs 2025; 27:5-18. [PMID: 39382819 DOI: 10.1007/s40272-024-00653-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/23/2024] [Indexed: 10/10/2024]
Abstract
Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematological malignancies, inducing notable and durable clinical responses. However, for solid tumors, including but not limited to pediatric tumors, several peculiar biological features posed substantial challenges for achieving comparable results. Despite sound pre-clinical evidence of the ability of CAR T cells to eradicate solid malignancies, their activity remains suboptimal when facing the in vivo complexity of solid tumors, characterized by antigen heterogeneity, scarce T-cell infiltration, and an immunosuppressive microenvironment. Neuroblastoma was amongst the first tumors to be evaluated as a potential candidate for GD2-targeting CAR T cells, which recently documented promising results in high-risk, heavily pre-treated patients. Moreover, innovative engineering strategies for generating more potent and persistent CAR T cells suggest the possibility to reproduce, and potentially improve, these promising results on a larger scale. In the next years, harnessing the full therapeutic potential of CAR T cells and other immunotherapeutic strategies may open new possibilities for effectively treating the most aggressive forms of pediatric tumors.
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Affiliation(s)
- Gabriele Canciani
- Department of Hematology, Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
- Residency School of Pediatrics, University of Rome Tor Vergata, Rome, Italy
| | - Francesco Fabozzi
- Department of Hematology, Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Claudia Pinacchio
- Department of Hematology, Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Manuela Ceccarelli
- Department of Hematology, Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Francesca Del Bufalo
- Department of Hematology, Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
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15
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Park S, Maus MV, Choi BD. CAR-T cell therapy for the treatment of adult high-grade gliomas. NPJ Precis Oncol 2024; 8:279. [PMID: 39702579 DOI: 10.1038/s41698-024-00753-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 10/30/2024] [Indexed: 12/21/2024] Open
Abstract
Treatment for malignant primary brain tumors, including glioblastoma, remains a significant challenge despite advances in therapy. CAR-T cell immunotherapy represents a promising alternative to conventional treatments. This review discusses the landscape of clinical trials for CAR-T cell therapy targeting brain tumors, highlighting key advancements like novel target antigens and combinatorial strategies designed to address tumor heterogeneity and immunosuppression, with the goal of improving outcomes for patients with these aggressive cancers.
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Affiliation(s)
- Sangwoo Park
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Marcela V Maus
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Bryan D Choi
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Brain Tumor Immunotherapy Lab, Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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16
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van der Schans JJ, Katsarou A, Kladis G, Bar C, Ramirez MM, Themeli M, Mutis T. A convenient viral transduction based method for advanced multi-engineering of primary human (CAR) T-cells. J Genet Eng Biotechnol 2024; 22:100446. [PMID: 39674638 PMCID: PMC11629549 DOI: 10.1016/j.jgeb.2024.100446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 11/08/2024] [Accepted: 11/14/2024] [Indexed: 12/16/2024]
Abstract
The past decades have illustrated the power of T-cell engineering in the development of new and successful cell therapies, such as chimeric antigen receptor (CAR) T-cells. Despite clinical success in hematological malignancies, it also becomes increasingly clear that additional T-cell engineering will be required to improve efficacy and safety and expand the application to solid tumors. Engineering is most often achieved by viral delivery of transgenes, however, viral vector capacity limitations make efficient and reproducible generation of multi transgene expressing T-cell therapeutics technically challenging. We here describe a convenient and efficient method for the delivery of up to three γ-retroviral CAR vectors in T-cells. We achieved this using virus vector mixtures that are simultaneously produced at high titers by double- or triple- transduced stable virus producer cells. We show that this method is superior in overall efficiency and reproducibility to conventional double or triple CAR transductions, in which separate viral batches are used. Due to its robustness, this method can facilitate the research and the development for advanced T-cell engineering towards more effective and safe therapies.
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Affiliation(s)
- Jort J van der Schans
- Department of Hematology, Amsterdam UMC, Location VU University Medical Center, Cancer Center Amsterdam, Room CCA3.38, De Boelelaan 1117, Amsterdam 1081 HV, the Netherlands.
| | - Afroditi Katsarou
- Department of Hematology, Amsterdam UMC, Location VU University Medical Center, Cancer Center Amsterdam, Room CCA3.38, De Boelelaan 1117, Amsterdam 1081 HV, the Netherlands
| | - George Kladis
- Department of Hematology, Amsterdam UMC, Location VU University Medical Center, Cancer Center Amsterdam, Room CCA3.38, De Boelelaan 1117, Amsterdam 1081 HV, the Netherlands
| | - Citlali Bar
- Department of Hematology, Amsterdam UMC, Location VU University Medical Center, Cancer Center Amsterdam, Room CCA3.38, De Boelelaan 1117, Amsterdam 1081 HV, the Netherlands
| | - Max Medina Ramirez
- Department of Hematology, Amsterdam UMC, Location VU University Medical Center, Cancer Center Amsterdam, Room CCA3.38, De Boelelaan 1117, Amsterdam 1081 HV, the Netherlands
| | - Maria Themeli
- Department of Hematology, Amsterdam UMC, Location VU University Medical Center, Cancer Center Amsterdam, Room CCA3.38, De Boelelaan 1117, Amsterdam 1081 HV, the Netherlands
| | - Tuna Mutis
- Department of Hematology, Amsterdam UMC, Location VU University Medical Center, Cancer Center Amsterdam, Room CCA3.38, De Boelelaan 1117, Amsterdam 1081 HV, the Netherlands
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17
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Trautmann T, Yakobian N, Nguyen R. CAR T-cells for pediatric solid tumors: where to go from here? Cancer Metastasis Rev 2024; 43:1445-1461. [PMID: 39317919 PMCID: PMC11554711 DOI: 10.1007/s10555-024-10214-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 09/13/2024] [Indexed: 09/26/2024]
Abstract
Despite the great success that chimeric antigen receptor (CAR) T-cells have had in patients with B-cell malignancies and multiple myeloma, they continue to have limited efficacy against most solid tumors. Especially in the pediatric population, pre- and post-treatment biopsies are rarely performed due to ethical reasons, and thus, our understanding is still very limited regarding the mechanisms in the tumor microenvironment by which tumor cells exclude effectors and attract immune-suppressive cells. Nevertheless, based on the principles that are known, current T-cell engineering has leveraged some of these processes and created more potent CAR T-cells. The recent discovery of new oncofetal antigens and progress made in CAR design have expanded the potential pool of candidate antigens for therapeutic development. The most promising approaches to enhance CAR T-cells are novel CAR gating strategies, creative ways of cytokine delivery to the TME without enhancing systemic toxicity, and hijacking the chemokine axis of tumors for migratory purposes. With these new modifications, the next step in the era of CAR T-cell development will be the clinical validation of these promising preclinical findings.
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Affiliation(s)
- Tina Trautmann
- Pediatric Oncology Branch, NCI, NIH, NCI, 10 Center Drive, 1W-5832, Bethesda, MD, 20892, USA
| | - Natalia Yakobian
- Pediatric Oncology Branch, NCI, NIH, NCI, 10 Center Drive, 1W-5832, Bethesda, MD, 20892, USA
| | - Rosa Nguyen
- Pediatric Oncology Branch, NCI, NIH, NCI, 10 Center Drive, 1W-5832, Bethesda, MD, 20892, USA.
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18
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Carcopino C, Erdogan E, Henrich M, Kobold S. Armoring chimeric antigen receptor (CAR) T cells as micropharmacies for cancer therapy. IMMUNO-ONCOLOGY TECHNOLOGY 2024; 24:100739. [PMID: 39711794 PMCID: PMC11659983 DOI: 10.1016/j.iotech.2024.100739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
Chimeric antigen receptor (CAR)-T-cell therapy has emerged as a powerful weapon in the fight against cancer. However, its efficacy is often hindered by challenges such as limited tumor penetration, antigen escape, and immune suppression within the tumor microenvironment. This review explores the potential of armored CAR-T cells, or 'micropharmacies', in overcoming these obstacles and enhancing the therapeutic outcomes of adoptive T-cell (ATC) therapy. We delve into the engineering strategies behind these advanced therapies and the mechanisms through which they improve CAR-T-cell efficacy. Additionally, we discuss the latest advancements and research findings in the field, providing a comprehensive understanding of the role of armored CAR-T cells in cancer treatment. Ultimately, this review highlights the promising future of integrating micropharmacies into ATC therapy, paving the way for more effective and targeted cancer treatments.
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Affiliation(s)
- C. Carcopino
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Munich, Germany
| | - E. Erdogan
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Munich, Germany
| | - M. Henrich
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Munich, Germany
| | - S. Kobold
- Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University (LMU) of Munich, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, a partnership between the DKFZ Heidelberg and the University Hospital of the LMU, Heidelberg, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
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19
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Alsalloum A, Alrhmoun S, Perik-Zavosdkaia O, Fisher M, Volynets M, Lopatnikova J, Perik-Zavodskii R, Shevchenko J, Philippova J, Solovieva O, Zavjalov E, Kurilin V, Shiku H, Silkov A, Sennikov S. Decoding NY-ESO-1 TCR T cells: transcriptomic insights reveal dual mechanisms of tumor targeting in a melanoma murine xenograft model. Front Immunol 2024; 15:1507218. [PMID: 39660132 PMCID: PMC11628372 DOI: 10.3389/fimmu.2024.1507218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 11/08/2024] [Indexed: 12/12/2024] Open
Abstract
The development of T cell receptor-engineered T cells (TCR-T) targeting intracellular antigens is a promising strategy for treating solid tumors; however, the mechanisms underlying their effectiveness remain poorly understood. In this study, we employed advanced techniques to investigate the functional state of T cells engineered with retroviral vectors to express a TCR specific for the NY-ESO-1 157-165 peptide in the HLA-A*02:01 context. Flow cytometry revealed a predominance of naïve T cells. Gene expression profiling using NanoString technology revealed upregulation of genes encoding chemokine receptors CCR2 and CCR5, indicating enhanced migration towards tumor sites. In the SK-Mel-37 xenograft model, these transduced T cells achieved complete tumor eradication. Furthermore, single-cell RNA sequencing (scRNA-seq) conducted 14 days post-TCR T cell infusion provided a comprehensive analysis of the in vivo adaptation of these cells, identifying a distinct subset of CD8+ effector T cells with an NK cell-like gene expression profile. Our findings indicate that NY-ESO-1 TCR-transduced T cells have the potential to mediate dual antitumor effects through both antigen-independent NK-like and antigen-specific CTL-like responses. This study underscores the potential of NY-ESO-1 TCR-T cells as potent tumor-eradicating agents, highlighting the importance of harnessing their versatile functional capabilities to refine and enhance therapeutic strategies.
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MESH Headings
- Animals
- Humans
- Mice
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/genetics
- Transcriptome
- Immunotherapy, Adoptive/methods
- Cell Line, Tumor
- Melanoma/therapy
- Melanoma/immunology
- Melanoma/genetics
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/immunology
- Xenograft Model Antitumor Assays
- HLA-A2 Antigen/genetics
- HLA-A2 Antigen/immunology
- CD8-Positive T-Lymphocytes/immunology
- Membrane Proteins/genetics
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/immunology
- Gene Expression Profiling
- Neoplasm Proteins
- Peptide Fragments
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Affiliation(s)
- Alaa Alsalloum
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
- Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia
| | - Saleh Alrhmoun
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
- Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia
| | - Olga Perik-Zavosdkaia
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Marina Fisher
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Marina Volynets
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Julia Lopatnikova
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Roman Perik-Zavodskii
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Julia Shevchenko
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Julia Philippova
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Olga Solovieva
- Center for Collective Use SPF-vivarium ICG SB RAS, Ministry of Science and High Education of Russian Federation, Novosibirsk, Russia
| | - Evgenii Zavjalov
- Center for Collective Use SPF-vivarium ICG SB RAS, Ministry of Science and High Education of Russian Federation, Novosibirsk, Russia
| | - Vasily Kurilin
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Hiroshi Shiku
- Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu, Japan
| | - Alexander Silkov
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Sergey Sennikov
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
- Department of Immunology, V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, Novosibirsk, Russia
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20
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Lv R, Guo Y, Liu W, Dong G, Liu X, Li C, Ren Y, Zhang Z, Neo SY, Mao W, Wu J. Revolutionizing cancer treatment: the emerging potential and potential challenges of in vivo self-processed CAR cell therapy. Theranostics 2024; 14:7424-7447. [PMID: 39659573 PMCID: PMC11626932 DOI: 10.7150/thno.101941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 10/23/2024] [Indexed: 12/12/2024] Open
Abstract
Chimeric antigen receptor (CAR) cell immunotherapies, including CAR-T, CAR-Macrophages, CAR-Natural Killer, CAR-γδ T, etc., have demonstrated significant advancements in the treatment of both hematologic malignancies and solid tumors. Despite the notable successes of traditional CAR cell manufacturing, its application remains constrained by the complicated production process and expensive costs. Consequently, efforts are focused on streamlining CAR cell production to enhance efficacy and accessibility. Among numerous proposed strategies, direct in vivo generation of CAR cells represents the most substantial technical challenge, yet holding great promise for achieving clinical efficacy. Herein, we outlined the current state-of-the-art in vivo CAR therapy, including CAR technology development, transfection vectors, and influence factors of construction of CAR in vivo. We also reviewed the types and characteristics of different delivery systems and summarized the advantages of in vivo CAR cell therapy, such as rapid preparation and cost-effectiveness. Finally, we discussed the limitations, including technical issues, challenges in target and signal design, and cell-related constraints. Meanwhile, strategies have correspondingly been proposed to advance the development of CAR cell therapy, in order to open the new horizons on cancer treatment.
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Affiliation(s)
- Ruijie Lv
- Department of Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital; Jinan 250014, China; School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Yanting Guo
- Department of Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital; Jinan 250014, China; School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Weici Liu
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu 214023, China
| | - Guangjian Dong
- Department of Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital; Jinan 250014, China; School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Xiangyin Liu
- Department of Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital; Jinan 250014, China; School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Caihui Li
- Department of Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital; Jinan 250014, China; School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Yi Ren
- Department of Clinical Pharmacy, School of Pharmacy, Shandong Second Medical University, Weifang, Shandong 261042, China
| | - Zipeng Zhang
- Medical Science and Technology Innovation Center Shandong First Medical University & Shandong Academy of Medical Sciences Jinan 250117, China
| | - Shi-Yong Neo
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Republic of Singapore
| | - Wenjun Mao
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu 214023, China
| | - Jing Wu
- Department of Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital; Jinan 250014, China; School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
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21
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Gupta A, Dagar G, Rehmani MU, Prasad CP, Saini D, Singh M, Shankar A. CAR T-cell therapy in cancer: Integrating nursing perspectives for enhanced patient care. Asia Pac J Oncol Nurs 2024; 11:100579. [PMID: 39315365 PMCID: PMC11417177 DOI: 10.1016/j.apjon.2024.100579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 08/21/2024] [Indexed: 09/25/2024] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy represents a significant advancement in cancer treatment, particularly for hematologic malignancies. Various cancer immunotherapy strategies are presently being explored, including cytokines, cancer vaccines, immune checkpoint inhibitors, immunomodulators monoclonal antibodies, etc. The therapy has shown impressive efficacy in treating conditions such as acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma, often leading to complete remission in refractory cases. However, the clinical application of CAR T-cell therapy is accompanied by challenges, notably severe side effects. Effective management of these adverse effects requires meticulous monitoring and prompt intervention, highlighting the critical role of nursing in this therapeutic process. Nurses play a crucial role in patient education, monitoring, symptom management, care coordination, and psychosocial support, ensuring safe and effective treatment. As research advances and new CAR T-cell therapies are developed, the role of nursing professionals remains pivotal in optimizing patient outcomes. The continued evolution of CAR T-cell therapy promises improved outcomes, with nursing professionals integral to its success.
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Affiliation(s)
- Ashna Gupta
- Department of Medical Oncology (Lab), Dr BR Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Delhi, India
| | - Gunjan Dagar
- Department of Medical Oncology (Lab), Dr BR Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Delhi, India
| | - Mohd Umar Rehmani
- Department of Medical Oncology (Lab), Dr BR Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Delhi, India
| | - Chandra Prakash Prasad
- Department of Medical Oncology (Lab), Dr BR Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Delhi, India
| | - Deepak Saini
- Indian Society of Clinical Oncology, Delhi, India
| | - Mayank Singh
- Department of Medical Oncology (Lab), Dr BR Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Delhi, India
| | - Abhishek Shankar
- Department of Radiation Oncology, Dr BR Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Delhi, India
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22
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Bhullar PK, Motaparthi K, Zieman DP, Johnson C, Gurnani P, Sokumbi O. Toxic epidermal necrolysis-like cutaneous toxicity following chimeric antigen receptor T-cell therapy in recurrent large B-cell lymphoma. J Cutan Pathol 2024; 51:767-772. [PMID: 38982730 DOI: 10.1111/cup.14687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 06/24/2024] [Accepted: 07/01/2024] [Indexed: 07/11/2024]
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable success in treating various B-cell malignancies, redirecting T-cell cytotoxicity toward cancer cells. Despite its efficacy, CAR-T therapy is associated with potential risks, including cytokine release syndrome (CRS) and cytopenia. We present a case of a 69-year-old man with diffuse large B-cell lymphoma treated with axicabtagene-ciloleucel CAR-T therapy, who developed a rare and severe cutaneous toxicity resembling toxic epidermal necrolysis (TEN). The patient exhibited persistent fevers, CRS, and subsequent development of a widespread erythematous macular eruption, progressing to vesiculation with bullae. Notably, allopurinol-induced TEN was considered with the patient's recent exposure to allopurinol, although the onset and minimal mucosal involvement did not align with typical presentations of allopurinol-induced cases. The cutaneous reaction, distinct from typical SJS/TEN, showed minimal mucosal involvement and coincided with the cytokine release storm, differing from allopurinol-induced TEN. Despite the absence of guidelines, the patient was managed with systemic steroids, achieving significant improvement. This case expands the spectrum of CAR-T therapy-related cutaneous toxicities, highlighting the need for early recognition of histopathology and tailored management by dermatologists. Further understanding of these reactions is crucial for optimizing the safety profile of this groundbreaking immunotherapy.
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Affiliation(s)
- Puneet K Bhullar
- Department of Dermatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Kiran Motaparthi
- Department of Dermatology, University of Florida, Gainesville, Florida, USA
| | - Daniel P Zieman
- Department of Dermatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Cassandra Johnson
- Department of Dermatology, University of Florida, Gainesville, Florida, USA
| | - Pooja Gurnani
- Department of Dermatology, University of Florida, Gainesville, Florida, USA
| | - Olayemi Sokumbi
- Department of Dermatology, Mayo Clinic, Jacksonville, Florida, USA
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23
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Deo AS, Shrijana, S U S, Karun S, Bisaria K, Sarkar K. Participation of T cells in generating immune protection against cancers. Pathol Res Pract 2024; 262:155534. [PMID: 39180801 DOI: 10.1016/j.prp.2024.155534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 08/09/2024] [Accepted: 08/11/2024] [Indexed: 08/27/2024]
Abstract
T cells are essential to the immune system's reaction. The major job of the immune system is to identify and get rid of any abnormal or malignant cells in the body. White blood cells called T cells coordinate and carry out immunological responses, including identifying and eliminating cancer cells. It mostly consists of two types called helper T-cells and cytotoxic T-cells. Together, they create an efficient reaction against cancer. Both the primary T cell subtype - CD4+ and CD8+ Tcells have specific role to play in our immune system.CD4+ T cells are limited to MHC-II molecules and acts as helper cell by activating and enhancing other immune cells. On the other side CD8+ T cells are called the killer cells as they eradicate the abnormal and contaminated cells and are limited to MHC-I molecules. The malignant cells are destroyed when cytotoxic T cells come into direct contact with them. This happens via number of processes, including TCR recognition, the release of cytotoxic chemicals, and finally the activation of the immune system. T cell receptors on the surface of cytotoxic T cells allow them to identify tumour cells and these T cells release harmful chemicals like perforins and granzymes when they connect to malignant cells. T-cells that have been stimulated release cytokines such as gamma interferon. T-cells can also acquire memory responses that improve their capacity for recognition and response. Helper T-cells contribute to the development of an immune response. It entails coordination and activation as well as the enlistment of additional immune cells, including macrophages and natural killer cells, to assist in the eradication of cancer cells. Despite the fact that the cancer frequently creates defence systems to circumvent their immune response. Together, these activities support the immune surveillance and T-cell-mediated regulation of cancer cells. Treatments like chemotherapy, radiation, and surgery are main ways to treat cancer but immunotherapy has been emerging since last few decades. These immune specific treatments have shown huge positive result. CAR T cell therapy is a promising weapon to fight again blood cancer and it works by focusing on our immune system to fight and eliminate cancer.
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Affiliation(s)
- Anisha Singha Deo
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Shrijana
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Sruthika S U
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Shreya Karun
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Kashish Bisaria
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Koustav Sarkar
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India.
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24
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Bartoszewska E, Tota M, Kisielewska M, Skowron I, Sebastianka K, Stefaniak O, Molik K, Rubin J, Kraska K, Choromańska A. Overcoming Antigen Escape and T-Cell Exhaustion in CAR-T Therapy for Leukemia. Cells 2024; 13:1596. [PMID: 39329777 PMCID: PMC11430486 DOI: 10.3390/cells13181596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/18/2024] [Accepted: 09/20/2024] [Indexed: 09/28/2024] Open
Abstract
Leukemia is a prevalent pediatric cancer with significant challenges, particularly in relapsed or refractory cases. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a personalized cancer treatment, modifying patients' T cells to target and destroy resistant cancer cells. This study reviews the current therapeutic options of CAR-T therapy for leukemia, addressing the primary obstacles such as antigen escape and T-cell exhaustion. We explore dual-targeting strategies and their potential to improve treatment outcomes by preventing the loss of target antigens. Additionally, we examine the mechanisms of T-cell exhaustion and strategies to enhance CAR-T persistence and effectiveness. Despite remarkable clinical successes, CAR-T therapy poses risks such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Our findings highlight the need for ongoing research to optimize CAR-T applications, reduce toxicities, and extend this innovative therapy to a broader range of hematologic malignancies. This comprehensive review aims to provide valuable insights for improving leukemia treatment and advancing the field of cancer immunotherapy.
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Affiliation(s)
- Elżbieta Bartoszewska
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Maciej Tota
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Monika Kisielewska
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Izabela Skowron
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Kamil Sebastianka
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Oliwia Stefaniak
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Klaudia Molik
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Jakub Rubin
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Karolina Kraska
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland (M.K.); (I.S.); (K.S.); (O.S.); (K.M.); (J.R.); (K.K.)
- Student Research Group No K148, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Anna Choromańska
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
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Schoenfeld K, Habermann J, Wendel P, Harwardt J, Ullrich E, Kolmar H. T cell receptor-directed antibody-drug conjugates for the treatment of T cell-derived cancers. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200850. [PMID: 39176070 PMCID: PMC11338945 DOI: 10.1016/j.omton.2024.200850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 07/02/2024] [Accepted: 07/16/2024] [Indexed: 08/24/2024]
Abstract
T cell-derived cancers are hallmarked by heterogeneity, aggressiveness, and poor clinical outcomes. Available targeted therapies are severely limited due to a lack of target antigens that allow discrimination of malignant from healthy T cells. Here, we report a novel approach for the treatment of T cell diseases based on targeting the clonally rearranged T cell receptor displayed by the cancerous T cell population. As a proof of concept, we identified an antibody with unique specificity toward a distinct T cell receptor (TCR) and developed antibody-drug conjugates, precisely recognizing and eliminating target T cells while preserving overall T cell repertoire integrity and cellular immunity. Our anti-TCR antibody-drug conjugates demonstrated effective receptor-mediated cell internalization, associated with induction of cancer cell death with strong signs of apoptosis. Furthermore, cell proliferation-inhibiting bystander effects observed on target-negative cells may contribute to the molecules' anti-tumor properties precluding potential tumor escape mechanisms. To our knowledge, this represents the first anti-TCR antibody-drug conjugate designed as custom-tailored immunotherapy for T cell-driven pathologies.
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Affiliation(s)
- Katrin Schoenfeld
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, 64287 Darmstadt, Germany
| | - Jan Habermann
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, 64287 Darmstadt, Germany
- Goethe University, Department of Pediatrics, Experimental Immunology and Cell Therapy, 60590 Frankfurt am Main, Germany
- Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany
| | - Philipp Wendel
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, 64287 Darmstadt, Germany
- Goethe University, Department of Pediatrics, Experimental Immunology and Cell Therapy, 60590 Frankfurt am Main, Germany
- Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany
- German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, 60590 Frankfurt am Main, Germany
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Julia Harwardt
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, 64287 Darmstadt, Germany
| | - Evelyn Ullrich
- Goethe University, Department of Pediatrics, Experimental Immunology and Cell Therapy, 60590 Frankfurt am Main, Germany
- Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany
- German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, 60590 Frankfurt am Main, Germany
| | - Harald Kolmar
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, 64287 Darmstadt, Germany
- Centre for Synthetic Biology, Technical University of Darmstadt, 64283 Darmstadt, Germany
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26
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Miller A, Daum R, Wang T, Wu M, Tat C, Pfeiffer T, Navai S, Heczey A, Hegde M, Ahmed N, Whittle SB, Hill L, Martinez C, Krance R, Ramos CA, Rouce RH, Lulla P, Heslop HE, Omer B, Shekar M. Prolonged cytopenias after immune effector cell therapy and lymphodepletion in patients with leukemia, lymphoma and solid tumors. Cytotherapy 2024; 26:1026-1032. [PMID: 38819365 PMCID: PMC11344664 DOI: 10.1016/j.jcyt.2024.04.075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 04/10/2024] [Accepted: 04/29/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND AIMS The success of chimeric antigen receptor (CAR) T-cell therapy in treating B-cell malignancies has led to the evaluation of CAR T-cells targeting a variety of other malignancies. Although the efficacy of CAR T-cells is enhanced when administered post-lymphodepleting chemotherapy, this can trigger bone marrow suppression and sustained cytopenia after CD19.CAR T-cell therapy. Additionally, systemic inflammation associated with CAR T-cell activity may contribute to myelosuppression. Cytopenias, such as neutropenia and thrombocytopenia, elevate the risk of severe infections and bleeding, respectively. However, data on the incidence of prolonged cytopenias after immune effector therapy in the solid tumor context remain limited. OBJECTIVE We compared the incidence of prolonged cytopenias after immune effector therapy including genetically modified T-cells, virus-specific T-cells (VSTs) and NKT-cells, as well non-gene-modified VSTs for leukemia, lymphoma, and solid tumors (ST) to identify associated risk factors. METHODS A retrospective analysis was conducted of 112 pediatric and adult patients with relapsed and/or refractory cancers who received lymphodepleting chemotherapy followed by immune effector therapy. Patients treated with 13 distinct immune effector cell therapies through 11 single-center clinical trials and 2 commercial products over a 6-year period were categorized into 3 types of malignancies: leukemia, lymphoma and ST. We obtained baseline patient characteristics and adverse events data for each participant, and tracked neutrophil and platelet counts following lymphodepletion. RESULTS Of 112 patients, 104 (92.9%) experienced cytopenias and 88 (79%) experienced severe cytopenias. Patients with leukemia experienced significantly longer durations of severe neutropenia (median duration of 14 days) compared with patients with lymphoma (7 days) or ST (11 days) (P = 0.002). Patients with leukemia also had a higher incidence of severe thrombocytopenia (74.1%), compared with lymphoma (46%, P = 0.03) and ST (14.3%, P < 0.0001). Prolonged cytopenias were significantly associated with disease type (63% of patients with leukemia, 44% of patients with lymphoma, and 22.9% of patients with ST, P = 0.006), prior hematopoietic stem cell transplant (HSCT) (66.7% with prior HSCT versus 38.3% without prior HSCT, P = 0.039), and development of immune effector cell-associated neurotoxicity syndrome (ICANS) (75% with ICANS versus 38% without ICANS, P = 0.027). There was no significant association between prolonged cytopenias and cytokine release syndrome. CONCLUSIONS Immune effector recipients often experience significant cytopenias due to marrow suppression following lymphodepletion regardless of disease, but prolonged severe cytopenias are significantly less common after treatment of patients with lymphoma and solid tumors.
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Affiliation(s)
- Anne Miller
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA
| | - Rachel Daum
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dell Medical School, University of Texas at Austin, Austin, TX, USA
| | - Tao Wang
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA
| | - Mengfen Wu
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA
| | - Candise Tat
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA
| | - Thomas Pfeiffer
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA; Department of Pediatrics, Division of Hematology/Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Shoba Navai
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA
| | - Andras Heczey
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA
| | - Meenakshi Hegde
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA
| | - Nabil Ahmed
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
| | - Sarah B Whittle
- Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA
| | - LaQuisa Hill
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA
| | - Caridad Martinez
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA
| | - Robert Krance
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA
| | - Carlos A Ramos
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA
| | - Rayne H Rouce
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA
| | - Premal Lulla
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA
| | - Helen E Heslop
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA
| | - Bilal Omer
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA
| | - Meghan Shekar
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA.
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27
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Nunoya JI, Imuta N, Masuda M. Chimeric Antigen Receptor T Cell Bearing Herpes Virus Entry Mediator Co-Stimulatory Signal Domain Exhibits Exhaustion-Resistant Properties. Int J Mol Sci 2024; 25:8662. [PMID: 39201348 PMCID: PMC11354286 DOI: 10.3390/ijms25168662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 08/06/2024] [Accepted: 08/07/2024] [Indexed: 09/02/2024] Open
Abstract
Improving chimeric antigen receptor (CAR)-T cell therapeutic outcomes and expanding its applicability to solid tumors requires further refinement of CAR-T cells. We previously reported that CAR-T cells bearing a herpes virus entry mediator (HVEM)-derived co-stimulatory signal domain (CSSD) (HVEM-CAR-T cells) exhibit superior functions and characteristics. Here, we conducted comparative analyses to evaluate the impact of different CSSDs on CAR-T cell exhaustion. The results indicated that HVEM-CAR-T cells had significantly lower frequencies of exhausted cells and exhibited the highest proliferation rates upon antigenic stimulation. Furthermore, proliferation inhibition by programmed cell death ligand 1 was stronger in CAR-T cells bearing CD28-derived CSSD (CD28-CAR-T cells) whereas it was weaker in HVEM-CAR-T. Additionally, HVEM-CAR-T cells maintained a low exhaustion level even after antigen-dependent proliferation and exhibited potent killing activities, suggesting that HVEM-CAR-T cells might be less prone to early exhaustion. Analysis of CAR localization on the cell surface revealed that CAR formed clusters in CD28-CAR-T cells whereas uniformly distributed in HVEM-CAR-T cells. Analysis of CD3ζ phosphorylation indicated that CAR-dependent tonic signals were strongly sustained in CD28-CAR-T cells whereas they were significantly weaker in HVEM-CAR-T cells. Collectively, these results suggest that the HVEM-derived CSSD is useful for generating CAR-T cells with exhaustion-resistant properties, which could be effective against solid tumors.
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Affiliation(s)
- Jun-ichi Nunoya
- Department of Microbiology, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan (M.M.)
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28
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Dai R, Uppot R, Arellano R, Kalva S. Image-guided Ablative Procedures. Clin Oncol (R Coll Radiol) 2024; 36:484-497. [PMID: 38087706 DOI: 10.1016/j.clon.2023.11.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 09/19/2023] [Accepted: 11/21/2023] [Indexed: 07/09/2024]
Abstract
Various image-guided ablative procedures include chemical and thermal ablation techniques and irreversible electroporation. These have been used for curative intent for small tumours and palliative intent for debulking, immunogenicity and pain control. Understanding these techniques is critical to avoiding complications and achieving superior clinical outcomes. Additionally, combination with immunotherapy and chemotherapies is rapidly evolving. There are numerous opportunities in interventional radiology to advance ablation techniques and seamlessly integrate into current treatment regimens for both benign and malignant tumours.
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Affiliation(s)
- R Dai
- Massachusetts General Hospital, Department of Radiology, Division of Intervention Radiology, Boston, Massachusetts, USA.
| | - R Uppot
- Massachusetts General Hospital, Department of Radiology, Division of Intervention Radiology, Boston, Massachusetts, USA
| | - R Arellano
- Massachusetts General Hospital, Department of Radiology, Division of Intervention Radiology, Boston, Massachusetts, USA
| | - S Kalva
- Massachusetts General Hospital, Department of Radiology, Division of Intervention Radiology, Boston, Massachusetts, USA
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Tian M, Wei JS, Cheuk ATC, Milewski D, Zhang Z, Kim YY, Chou HC, Liu C, Badr S, Pope EG, Rahmy A, Wu JT, Kelly MC, Wen X, Khan J. CAR T-cells targeting FGFR4 and CD276 simultaneously show potent antitumor effect against childhood rhabdomyosarcoma. Nat Commun 2024; 15:6222. [PMID: 39043633 PMCID: PMC11266617 DOI: 10.1038/s41467-024-50251-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 07/02/2024] [Indexed: 07/25/2024] Open
Abstract
Chimeric antigen receptor (CAR) T-cells targeting Fibroblast Growth Factor Receptor 4 (FGFR4), a highly expressed surface tyrosine receptor in rhabdomyosarcoma (RMS), are already in the clinical phase of development, but tumour heterogeneity and suboptimal activation might hamper their potency. Here we report an optimization strategy of the co-stimulatory and targeting properties of a FGFR4 CAR. We replace the CD8 hinge and transmembrane domain and the 4-1BB co-stimulatory domain with those of CD28. The resulting CARs display enhanced anti-tumor activity in several RMS xenograft models except for an aggressive tumour cell line, RMS559. By searching for a direct target of the RMS core-regulatory transcription factor MYOD1, we identify another surface protein, CD276, as a potential target. Bicistronic CARs (BiCisCAR) targeting both FGFR4 and CD276, containing two distinct co-stimulatory domains, have superior prolonged persistent and invigorated anti-tumor activities compared to the optimized FGFR4-specific CAR and the other BiCisCAR with the same 4-1BB co-stimulatory domain. Our study thus lays down the proof-of-principle for a CAR T-cell therapy targeting both FGFR4 and CD276 in RMS.
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MESH Headings
- Receptor, Fibroblast Growth Factor, Type 4/metabolism
- Receptor, Fibroblast Growth Factor, Type 4/genetics
- Rhabdomyosarcoma/therapy
- Rhabdomyosarcoma/immunology
- Rhabdomyosarcoma/genetics
- Humans
- Animals
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/metabolism
- Cell Line, Tumor
- Xenograft Model Antitumor Assays
- Mice
- Immunotherapy, Adoptive/methods
- B7 Antigens/metabolism
- B7 Antigens/immunology
- B7 Antigens/genetics
- MyoD Protein/metabolism
- MyoD Protein/genetics
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Child
- Female
- Mice, SCID
- Mice, Inbred NOD
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Affiliation(s)
- Meijie Tian
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jun S Wei
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Adam Tai-Chi Cheuk
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - David Milewski
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Zhongmei Zhang
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Yong Yean Kim
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Hsien-Chao Chou
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Can Liu
- Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, 20892, USA
| | - Sherif Badr
- Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Eleanor G Pope
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Abdelrahman Rahmy
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jerry T Wu
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Michael C Kelly
- Single Cell Analysis Facility, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Xinyu Wen
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Javed Khan
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
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30
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Han J, Liu H, Chen J, Jia K, Sun J, Nie Z. Chirality-Dependent Reprogramming of Macrophages. ACS NANO 2024. [PMID: 39011629 DOI: 10.1021/acsnano.4c04137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/17/2024]
Abstract
The chirality of materials directly influences their transport and biological effects in physiological conditions. However, the impact of chiral materials on cellular metabolic reprogramming remains incompletely elucidated. In this study, we have synthesized chiral gold particles through a light-driven particle growth approach and demonstrated that d-Au particles exhibited superior macrophage activation ability compared to l-Au particles. An inflammatory creatine-phosphocreatine shunt was induced following d-Au stimulation. This shunt, facilitated by the upregulated expression of creatine kinase muscle-type (CKM), also resulted in a reduction in cytosolic levels of creatine. Pharmacological inhibition and genetic ablation of CKM further suppressed the secretion of pro-inflammatory cytokines, without compromising mitochondrial respiration. Moreover, the activation of macrophages induced by d-Au was mediated through the activation of the NF-κB and NLRP3 inflammasome pathways. Inhibition of CKM expression not only decreased the secretion of CXCL2 but also attenuated IL-1β by suppressing the NLRP3 inflammasome pathways. Our investigation into the metabolic reprogramming mechanism of chiral materials on macrophage activation is pivotal for the application of chiral-based anticancer therapies.
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Affiliation(s)
- Jing Han
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences; Beijing 100190, China
| | - Huihui Liu
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences; Beijing 100190, China
| | - Junyu Chen
- Department of Clinical Laboratory, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Ke Jia
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences; Beijing 100190, China
- College of Chemical Engineering, Jiujiang University Jiujiang, Jiangxi Province 332005, China
| | - Jiameng Sun
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences; Beijing 100190, China
- College of Chemical Engineering, Jiujiang University Jiujiang, Jiangxi Province 332005, China
| | - Zongxiu Nie
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences; Beijing 100190, China
- School of Chemistry and Chemical Engineering, Ningxia University, Yinchuan, Ningxia 750021, China
- College of Chemical Engineering, Jiujiang University Jiujiang, Jiangxi Province 332005, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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31
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Schlegel LS, Werbrouck C, Boettcher M, Schlegel P. Universal CAR 2.0 to overcome current limitations in CAR therapy. Front Immunol 2024; 15:1383894. [PMID: 38962014 PMCID: PMC11219820 DOI: 10.3389/fimmu.2024.1383894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 06/03/2024] [Indexed: 07/05/2024] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapy has effectively complemented the treatment of advanced relapsed and refractory hematological cancers. The remarkable achievements of CD19- and BCMA-CAR T therapies have raised high expectations within the fields of hematology and oncology. These groundbreaking successes are propelling a collective aspiration to extend the reach of CAR therapies beyond B-lineage malignancies. Advanced CAR technologies have created a momentum to surmount the limitations of conventional CAR concepts. Most importantly, innovations that enable combinatorial targeting to address target antigen heterogeneity, using versatile adapter CAR concepts in conjunction with recent transformative next-generation CAR design, offer the promise to overcome both the bottleneck associated with CAR manufacturing and patient-individualized treatment regimens. In this comprehensive review, we delineate the fundamental prerequisites, navigate through pivotal challenges, and elucidate strategic approaches, all aimed at paving the way for the future establishment of multitargeted immunotherapies using universal CAR technologies.
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Affiliation(s)
- Lara Sophie Schlegel
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Coralie Werbrouck
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Michael Boettcher
- Department of Pediatric Surgery, University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Patrick Schlegel
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- Department of Pediatric Hematology and Oncology, Westmead Children’s Hospital, Sydney, NSW, Australia
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Peng BJ, Alvarado A, Cassim H, Guarneri S, Wong S, Willis J, SantaMaria J, Martynchuk A, Stratton V, Patel D, Chen CC, Li Y, Binder GK, Dryer-Minnerly R, Lee J, Basu S. Preclinical specificity & activity of a fully human 41BB-expressing anti-CD19 CART- therapy for treatment-resistant autoimmune disease. Mol Ther Methods Clin Dev 2024; 32:101267. [PMID: 38883975 PMCID: PMC11176803 DOI: 10.1016/j.omtm.2024.101267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 05/16/2024] [Indexed: 06/18/2024]
Abstract
Over 4% of the global population is estimated to live with autoimmune disease, necessitating immunosuppressive treatment that is often chronic, not curative, and carries associated risks. B cells have emerged as key players in disease pathogenesis, as evidenced by partial responsiveness to B cell depletion by antibody-based therapies. However, these treatments often have transient effects due to incomplete depletion of tissue-resident B cells. Chimeric antigen receptor (CAR) T cells targeting B cells have demonstrated efficacy in refractory systemic lupus erythematosus. To this end, we developed an anti-CD19 CAR T cell product candidate, CABA-201, containing a clinically evaluated fully human CD19 binder (IC78) with a 4-1BB costimulatory domain and CD3 zeta stimulation domain for treatment refractory autoimmune disease. Here, we demonstrate specific cytotoxic activity of CABA-201 against CD19+ Nalm6 cells with no off-target effects on primary human cells. Novel examination of CABA-201 generated from primary T cells from multiple patients with autoimmune disease displayed robust CAR surface expression and effective elimination of the intended target autologous CD19+ B cells in vitro. Together, these findings support the tolerability and activity of CABA-201 for clinical development in patients with autoimmune disease.
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Affiliation(s)
- Binghao J Peng
- Department of Cellular and Molecular Immunology, Cabaletta Bio, Philadelphia, PA 19130, USA
| | - Andrea Alvarado
- Department of Cellular and Molecular Immunology, Cabaletta Bio, Philadelphia, PA 19130, USA
| | - Hangameh Cassim
- Department of Cellular and Molecular Immunology, Cabaletta Bio, Philadelphia, PA 19130, USA
| | - Soprina Guarneri
- Department of Protein and Molecular Biology, Cabaletta Bio, Philadelphia, PA 19130, USA
| | - Steven Wong
- Department of Protein and Molecular Biology, Cabaletta Bio, Philadelphia, PA 19130, USA
| | - Jonathan Willis
- Department of Analytical Development, Cabaletta Bio, Philadelphia, PA 19130, USA
| | - Julia SantaMaria
- Department of Analytical Development, Cabaletta Bio, Philadelphia, PA 19130, USA
| | - Ashley Martynchuk
- Department of Manufacturing, Science, and Technologies, Cabaletta Bio, Philadelphia, PA 19130, USA
| | - Victoria Stratton
- Department of Manufacturing, Science, and Technologies, Cabaletta Bio, Philadelphia, PA 19130, USA
| | - Darshil Patel
- Department of Protein and Molecular Biology, Cabaletta Bio, Philadelphia, PA 19130, USA
| | - Chien-Chung Chen
- Department of Analytical Development, Cabaletta Bio, Philadelphia, PA 19130, USA
| | - Yan Li
- Department of Manufacturing, Science, and Technologies, Cabaletta Bio, Philadelphia, PA 19130, USA
| | | | | | - Jinmin Lee
- Department of Cellular and Molecular Immunology, Cabaletta Bio, Philadelphia, PA 19130, USA
| | - Samik Basu
- Cabaletta Bio, Philadelphia, PA 19130, USA
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33
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Chen D, Fuda F, Rosado F, Saumell S, John S, Chen M, Koduru P, Chen W. Clinicopathologic features of relapsed CD19(-) B-ALL in CD19-targeted immunotherapy: Biological insights into relapse and LILRB1 as a novel B-cell marker for CD19(-) B lymphoblasts. Int J Lab Hematol 2024; 46:503-509. [PMID: 38177979 DOI: 10.1111/ijlh.14226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 12/23/2023] [Indexed: 01/06/2024]
Abstract
INTRODUCTION The mechanism of relapsed CD19(-) B-ALL after anti-CD19 immunotherapy (Kymriah [CART-19] and blinatumomab) is under active investigation. Our study aims to assess LILRB1 as a novel B-cell marker for detecting CD19(-) B-lymphoblasts and to analyze the clinicopathologic/genetic features of such disease to provide biological insight into relapse. METHODS Six patients (3 males/3 females, median age of 14 years) with relapsed CD19(-) B-ALL were analyzed for cytogenetic/genetic profile and immunophenotype. RESULTS CD19(-) B-ALL emerged after an interval of 5.8 months following anti-CD19 therapy. Five of six patients had B-cell aplasia, indicative of a persistent effect of CART or blinatumomab at relapse. Importantly, LILRB1 was variably expressed on CD19(-) and CD19(+) B lymphoblasts, strong on CD34(+) lymphoblasts and dim/partial on CD34(-) lymphoblasts. Three of six patients with paired B-ALL samples (pre- and post-anti-CD19 therapy) carried complex and different cytogenetic abnormalities, either as completely different or sharing a subset of cytogenetic abnormalities. CONCLUSION LILRB1 can be used as a novel B-cell marker to identify CD19(-) B lymphoblasts. The emergence of CD19(-) B-ALL appears to be associated with complex cytogenetic evolutions. The mechanism of CD19(-) B-ALL relapse under anti-CD19 immune pressure remains to be explored by comprehensive molecular studies.
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Affiliation(s)
- Dong Chen
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Pathology and Laboratory Medicine, University of Connecticut, Farmington, Connecticut, USA
| | - Franklin Fuda
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Flavia Rosado
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Sílvia Saumell
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Hematology, Vall d'Hebron University Hospital, Experimental Hematology Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Samuel John
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Mingyi Chen
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Prasad Koduru
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Weina Chen
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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34
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Fox TA, Booth C. Improving access to gene therapy for rare diseases. Dis Model Mech 2024; 17:dmm050623. [PMID: 38639083 PMCID: PMC11051979 DOI: 10.1242/dmm.050623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2024] Open
Abstract
Effective gene therapy approaches have been developed for many rare diseases, including inborn errors of immunity and metabolism, haemoglobinopathies and inherited blindness. Despite successful pre-clinical and clinical results, these gene therapies are not widely available, primarily for non-medical reasons. Lack of commercial interest in therapies for ultra-rare diseases, costs of development and complex manufacturing processes required for advanced therapy medicinal products (ATMPs) are some of the main problems that are restricting access. The complexities and costs of navigating the regulatory environments in different jurisdictions for treatments that affect small numbers of patients is a problem unique to ATMPS for rare and ultra-rare diseases. In this Perspective, we outline some of the challenges and potential solutions that, we hope, will improve access to gene therapy for rare diseases.
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Affiliation(s)
- Thomas A. Fox
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, United Kingdom
| | - Claire Booth
- Infection, Immunity and Inflammation Department, UCL Great Ormond Street Institute of Child Health, UCL, London WC1N 1EH, UK
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Strüßmann T, Marks R, Wäsch R. Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Is There Still a Role for Autologous Stem Cell Transplantation in the CAR T-Cell Era? Cancers (Basel) 2024; 16:1987. [PMID: 38893108 PMCID: PMC11171011 DOI: 10.3390/cancers16111987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 05/21/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
Recently, CD19-directed chimeric antigen receptor (CAR) T-cell therapies have revolutionized treatment strategies for diffuse large B-cell lymphoma (DLBCL). CAR T-cell therapy is increasingly used as a second-line therapy for patients with DLBCL with early relapse or refractoriness to initial chemoimmunotherapy and displaced high-dose chemotherapy, followed by autologous stem cell transplantation (ASCT) as the standard of care for these patients. However, patients with late relapse or chemosensitive disease still benefit from autologous stem cell transplantation. We will review practice-changing studies in early relapse (ZUMA-7 and TRANSFORM) under consideration of the negative BELINDA trial, with a focus on register data, comparing CAR T-cell therapy and ASCT for patients responding to salvage therapy.
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Affiliation(s)
- Tim Strüßmann
- Department of Medicine I, Faculty of Medicine, Medical Center–University of Freiburg, University of Freiburg, 79106 Freiburg, Germany; (R.M.); (R.W.)
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Mahmood M, Taufiq I, Mazhar S, Hafeez F, Malik K, Afzal S. Revolutionizing personalized cancer treatment: the synergy of next-generation sequencing and CRISPR/Cas9. Per Med 2024; 21:175-190. [PMID: 38708901 DOI: 10.1080/17410541.2024.2341610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 04/08/2024] [Indexed: 05/07/2024]
Abstract
In the context of cancer heterogeneity, the synergistic action of next-generation sequencing (NGS) and CRISPR/Cas9 plays a promising role in the personalized treatment of cancer. NGS enables high-throughput genomic profiling of tumors and pinpoints specific mutations that primarily lead to cancer. Oncologists use this information obtained from NGS in the form of DNA profiling or RNA analysis to tailor precision strategies based on an individual's unique molecular signature. Furthermore, the CRISPR technique enables precise editing of cancer-specific mutations, allowing targeted gene modifications. Harnessing the potential insights of NGS and CRISPR/Cas9 heralds a remarkable frontier in cancer therapeutics with unprecedented precision, effectiveness and minimal off-target effects.
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Affiliation(s)
- Muniba Mahmood
- Centre for Excellence in Molecular Biology, University of the Punjab, Lahore, Punjab, 53700, Pakistan
| | - Izza Taufiq
- Centre for Excellence in Molecular Biology, University of the Punjab, Lahore, Punjab, 53700, Pakistan
| | - Sana Mazhar
- Centre for Excellence in Molecular Biology, University of the Punjab, Lahore, Punjab, 53700, Pakistan
| | - Faiqa Hafeez
- Centre for Excellence in Molecular Biology, University of the Punjab, Lahore, Punjab, 53700, Pakistan
| | - Kausar Malik
- Centre for Excellence in Molecular Biology, University of the Punjab, Lahore, Punjab, 53700, Pakistan
| | - Samia Afzal
- Centre for Excellence in Molecular Biology, University of the Punjab, Lahore, Punjab, 53700, Pakistan
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Tiwari P, Shukla RP, Yadav K, Panwar D, Agarwal N, Kumar A, Singh N, Bakshi AK, Marwaha D, Gautam S, Rai N, Mishra PR. Exploring nanocarriers as innovative materials for advanced drug delivery strategies in onco-immunotherapies. J Mol Graph Model 2024; 128:108702. [PMID: 38219505 DOI: 10.1016/j.jmgm.2024.108702] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 12/16/2023] [Accepted: 01/02/2024] [Indexed: 01/16/2024]
Abstract
In recent years, Onco-immunotherapies (OIMTs) have been shown to be a potential therapy option for cancer. Several immunotherapies have received regulatory approval, while many others are now undergoing clinical testing or are in the early stages of development. Despite this progress, a large number of challenges to the broad use of immunotherapies to treat cancer persists. To make immunotherapy more useful as a treatment while reducing its potentially harmful side effects, we need to know more about how to improve response rates to different types of immunotherapies. Nanocarriers (NCs) have the potential to harness immunotherapies efficiently, enhance the efficiency of these treatments, and reduce the severe adverse reactions that are associated with them. This article discusses the necessity to incorporate nanomedicines in OIMTs and the challenges we confront with current anti-OIMT approaches. In addition, it examines the most important considerations for building nanomedicines for OIMT, which may improve upon current immunotherapy methods. Finally, it highlights the applications and future scenarios of using nanotechnology.
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Affiliation(s)
- Pratiksha Tiwari
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India; Jawaharlal Nehru University, New Delhi, India
| | - Ravi Prakash Shukla
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Krishna Yadav
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Dilip Panwar
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Neha Agarwal
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Ankit Kumar
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Neha Singh
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Avijit Kumar Bakshi
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Disha Marwaha
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Shalini Gautam
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Nikhil Rai
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Prabhat Ranjan Mishra
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India; Academy of Scientific and Innovation Research (AcSIR), Ghaziabad, 201002, U.P., India.
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Chen X, Zhong S, Zhan Y, Zhang X. CRISPR-Cas9 applications in T cells and adoptive T cell therapies. Cell Mol Biol Lett 2024; 29:52. [PMID: 38609863 PMCID: PMC11010303 DOI: 10.1186/s11658-024-00561-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 03/15/2024] [Indexed: 04/14/2024] Open
Abstract
T cell immunity is central to contemporary cancer and autoimmune therapies, encompassing immune checkpoint blockade and adoptive T cell therapies. Their diverse characteristics can be reprogrammed by different immune challenges dependent on antigen stimulation levels, metabolic conditions, and the degree of inflammation. T cell-based therapeutic strategies are gaining widespread adoption in oncology and treating inflammatory conditions. Emerging researches reveal that clustered regularly interspaced palindromic repeats-associated protein 9 (CRISPR-Cas9) genome editing has enabled T cells to be more adaptable to specific microenvironments, opening the door to advanced T cell therapies in preclinical and clinical trials. CRISPR-Cas9 can edit both primary T cells and engineered T cells, including CAR-T and TCR-T, in vivo and in vitro to regulate T cell differentiation and activation states. This review first provides a comprehensive summary of the role of CRISPR-Cas9 in T cells and its applications in preclinical and clinical studies for T cell-based therapies. We also explore the application of CRISPR screen high-throughput technology in editing T cells and anticipate the current limitations of CRISPR-Cas9, including off-target effects and delivery challenges, and envisioned improvements in related technologies for disease screening, diagnosis, and treatment.
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Affiliation(s)
- Xiaoying Chen
- Department of Cardiology, Cardiovascular Institute of Zhengzhou University, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450003, China
| | - Shuhan Zhong
- Department of Hematology, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, 310003, China
| | - Yonghao Zhan
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450003, China.
| | - Xuepei Zhang
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450003, China.
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39
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Carrillo MA, Zhen A, Mu W, Rezek V, Martin H, Peterson CW, Kiem HP, Kitchen SG. Stem cell-derived CAR T cells show greater persistence, trafficking, and viral control compared to ex vivo transduced CAR T cells. Mol Ther 2024; 32:1000-1015. [PMID: 38414243 PMCID: PMC11163220 DOI: 10.1016/j.ymthe.2024.02.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 01/19/2024] [Accepted: 02/24/2024] [Indexed: 02/29/2024] Open
Abstract
Adoptive cell therapy (ACT) using T cells expressing chimeric antigen receptors (CARs) is an area of intense investigation in the treatment of malignancies and chronic viral infections. One of the limitations of ACT-based CAR therapy is the lack of in vivo persistence and maintenance of optimal cell function. Therefore, alternative strategies that increase the function and maintenance of CAR-expressing T cells are needed. In our studies using the humanized bone marrow/liver/thymus (BLT) mouse model and nonhuman primate (NHP) model of HIV infection, we evaluated two CAR-based gene therapy approaches. In the ACT approach, we used cytokine enhancement and preconditioning to generate greater persistence of anti-HIV CAR+ T cells. We observed limited persistence and expansion of anti-HIV CAR T cells, which led to minimal control of the virus. In our stem cell-based approach, we modified hematopoietic stem/progenitor cells (HSPCs) with anti-HIV CAR to generate anti-HIV CAR T cells in vivo. We observed CAR-expressing T cell expansion, which led to better plasma viral load suppression. HSPC-derived CAR cells in infected NHPs showed superior trafficking and persistence in multiple tissues. Our results suggest that a stem cell-based CAR T cell approach may be superior in generating long-term persistence and functional antiviral responses against HIV infection.
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Affiliation(s)
- Mayra A Carrillo
- Department of Medicine, Division of Hematology and Oncology, and UCLA AIDS Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Anjie Zhen
- Department of Medicine, Division of Hematology and Oncology, and UCLA AIDS Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Wenli Mu
- Department of Medicine, Division of Hematology and Oncology, and UCLA AIDS Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Valerie Rezek
- Department of Medicine, Division of Hematology and Oncology, and UCLA AIDS Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Heather Martin
- Department of Medicine, Division of Hematology and Oncology, and UCLA AIDS Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Christopher W Peterson
- Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA
| | - Hans-Peter Kiem
- Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA
| | - Scott G Kitchen
- Department of Medicine, Division of Hematology and Oncology, and UCLA AIDS Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Broad Stem Cell Research Center, Jonsson Comprehensive Cancer Center, and Molecular Biology Institute, UCLA, Los Angeles, CA, USA.
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Mishra A, Maiti R, Mohan P, Gupta P. Antigen loss following CAR-T cell therapy: Mechanisms, implications, and potential solutions. Eur J Haematol 2024; 112:211-222. [PMID: 37705357 DOI: 10.1111/ejh.14101] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 09/05/2023] [Accepted: 09/05/2023] [Indexed: 09/15/2023]
Abstract
Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a groundbreaking immunotherapeutic approach for treating various hematological malignancies. CAR-T cells are engineered to express synthetic receptors that target specific antigens on cancer cells, leading to their eradication. While the therapy has shown remarkable efficacy, a significant challenge that has been observed in 30%-70% of patients showing recurrent disease is antigen loss or downregulation. We searched PubMed/MEDLINE, EMBASE, and Google scholar for articles on antigen loss/escape following Chimeric antigen receptor T-cell therapy in malignancies. Antigen loss refers to the loss or reduction in the expression of the target antigen on cancer cells, rendering CAR-T cells ineffective. This phenomenon poses a significant clinical concern, as it can lead to disease relapse and limited treatment options. This review explores the mechanisms underlying antigen loss following CAR-T cell therapy, its implications on treatment outcomes, and potential strategies to overcome the problem.
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Affiliation(s)
- Archana Mishra
- Department of Pharmacology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Rituparna Maiti
- Department of Pharmacology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Prafull Mohan
- Clinical Pharmacologist, Armed Forces Medical Services, Guwahati, India
| | - Pooja Gupta
- Department of Pharmacology, All India Institute of Medical Sciences, Delhi, India
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Chatterjee G, Dhende P, Raj S, Shetty V, Ghogale S, Deshpande N, Girase K, Patil J, Kalra A, Narula G, Dalvi K, Dhamne C, Moulik NR, Rajpal S, Patkar NV, Banavali S, Gujral S, Subramanian PG, Tembhare PR. 15-color highly sensitive flow cytometry assay for post anti-CD19 targeted therapy (anti-CD19-CAR-T and blinatumomab) measurable residual disease assessment in B-lymphoblastic leukemia/lymphoma: Real-world applicability and challenges. Eur J Haematol 2024; 112:122-136. [PMID: 37706583 DOI: 10.1111/ejh.14102] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 09/04/2023] [Accepted: 09/05/2023] [Indexed: 09/15/2023]
Abstract
OBJECTIVES Measurable residual disease (MRD) is the most relevant predictor of disease-free survival in B-cell acute lymphoblastic leukemia (B-ALL). We aimed to establish a highly sensitive flow cytometry (MFC)-based B-ALL-MRD (BMRD) assay for patients receiving anti-CD19 immunotherapy with an alternate gating approach and to document the prevalence and immunophenotype of recurrently occurring low-level mimics and confounding populations. METHODS We standardized a 15-color highly-sensitive BMRD assay with an alternate CD19-free gating approach. The study included 137 MRD samples from 43 relapsed/refractory B-ALL patients considered for anti-CD19 immunotherapy. RESULTS The 15-color BMRD assay with CD22/CD24/CD81/CD33-based gating approach was routinely applicable in 137 BM samples and could achieve a sensitivity of 0.0005%. MRD was detected in 29.9% (41/137) samples with 31.7% (13/41) of them showing <.01% MRD. Recurrently occurring low-level cells that showed immunophenotypic overlap with leukemic B-blasts included: (a) CD19+CD10+CD34+CD22+CD24+CD81+CD123+CD304+ plasmacytoid dendritic cells, (b) CD73bright/CD304bright/CD81bright mesenchymal stromal/stem cells (CD10+) and endothelial cells (CD34+CD24+), (c) CD22dim/CD34+/CD38dim/CD81dim/CD19-/CD10-/CD24- early lymphoid progenitor/precursor type-1 cells (ELP-1) and (d) CD22+/CD34+/CD10heterogeneous/CD38moderate/CD81moderate/CD19-/CD24- stage-0 B-cell precursors or ELP-2 cells. CONCLUSIONS We standardized a highly sensitive 15-color BMRD assay with a non-CD19-based gating strategy for patients receiving anti-CD19 immunotherapy. We also described the immunophenotypes of recurrently occurring low-level populations that can be misinterpreted as MRD in real-world practice.
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Affiliation(s)
- Gaurav Chatterjee
- Hematopathology Laboratory, ACTREC, Tata Memorial Center, HBNI University, Navi Mumbai, Maharashtra, India
| | - Priyanka Dhende
- Hematopathology Laboratory, ACTREC, Tata Memorial Center, HBNI University, Navi Mumbai, Maharashtra, India
| | - Simpy Raj
- Hematopathology Laboratory, ACTREC, Tata Memorial Center, HBNI University, Navi Mumbai, Maharashtra, India
| | - Vruksha Shetty
- Hematopathology Laboratory, ACTREC, Tata Memorial Center, HBNI University, Navi Mumbai, Maharashtra, India
| | - Sitaram Ghogale
- Hematopathology Laboratory, ACTREC, Tata Memorial Center, HBNI University, Navi Mumbai, Maharashtra, India
| | - Nilesh Deshpande
- Hematopathology Laboratory, ACTREC, Tata Memorial Center, HBNI University, Navi Mumbai, Maharashtra, India
| | - Karishma Girase
- Hematopathology Laboratory, ACTREC, Tata Memorial Center, HBNI University, Navi Mumbai, Maharashtra, India
| | - Jagruti Patil
- Hematopathology Laboratory, ACTREC, Tata Memorial Center, HBNI University, Navi Mumbai, Maharashtra, India
| | - Aastha Kalra
- Hematopathology Laboratory, ACTREC, Tata Memorial Center, HBNI University, Navi Mumbai, Maharashtra, India
| | - Gaurav Narula
- Department of Pediatric Oncology, Tata Memorial Center, Mumbai, Mumbai, Maharashtra, India
| | - Kajal Dalvi
- Hematopathology Laboratory, ACTREC, Tata Memorial Center, HBNI University, Navi Mumbai, Maharashtra, India
| | - Chetan Dhamne
- Department of Pediatric Oncology, Tata Memorial Center, Mumbai, Mumbai, Maharashtra, India
| | - Nirmalya Roy Moulik
- Department of Pediatric Oncology, Tata Memorial Center, Mumbai, Mumbai, Maharashtra, India
| | - Sweta Rajpal
- Hematopathology Laboratory, ACTREC, Tata Memorial Center, HBNI University, Navi Mumbai, Maharashtra, India
| | - Nikhil V Patkar
- Hematopathology Laboratory, ACTREC, Tata Memorial Center, HBNI University, Navi Mumbai, Maharashtra, India
| | - Shripad Banavali
- Department of Pediatric Oncology, Tata Memorial Center, Mumbai, Mumbai, Maharashtra, India
| | - Sumeet Gujral
- Hematopathology Laboratory, Tata Memorial Center, Mumbai, Mumbai, Maharashtra, India
| | - Papagudi G Subramanian
- Hematopathology Laboratory, ACTREC, Tata Memorial Center, HBNI University, Navi Mumbai, Maharashtra, India
| | - Prashant R Tembhare
- Hematopathology Laboratory, ACTREC, Tata Memorial Center, HBNI University, Navi Mumbai, Maharashtra, India
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Canichella M, Molica M, Mazzone C, de Fabritiis P. Chimeric Antigen Receptor T-Cell Therapy in Acute Myeloid Leukemia: State of the Art and Recent Advances. Cancers (Basel) 2023; 16:42. [PMID: 38201469 PMCID: PMC10777995 DOI: 10.3390/cancers16010042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 12/07/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
Chimeric antigen receptors (CAR)-T-cell therapy represents the most important innovation in onco-hematology in recent years. The progress achieved in the management of complications and the latest generations of CAR-T-cells have made it possible to anticipate in second-line the indication of this type of treatment in large B-cell lymphoma. While some types of B-cell lymphomas and B-cell acute lymphoid leukemia have shown extremely promising results, the same cannot be said for myeloid leukemias-in particular, acute myeloid leukemia (AML), which would require innovative therapies more than any other blood disease. The heterogeneities of AML cells and the immunological complexity of the interactions between the bone marrow microenvironment and leukemia cells have been found to be major obstacles to the clinical development of CAR-T in AML. In this review, we report on the main results obtained in AML clinical trials, the preclinical studies testing potential CAR-T constructs, and future perspectives.
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Affiliation(s)
- Martina Canichella
- Hematology, St. Eugenio Hospital, ASL Roma2, 00144 Rome, Italy; (C.M.); (P.d.F.)
| | - Matteo Molica
- Department of Hematology-Oncology, Azienda Ospedaliera Pugliese-Ciaccio, 88100 Catanzaro, Italy;
| | - Carla Mazzone
- Hematology, St. Eugenio Hospital, ASL Roma2, 00144 Rome, Italy; (C.M.); (P.d.F.)
| | - Paolo de Fabritiis
- Hematology, St. Eugenio Hospital, ASL Roma2, 00144 Rome, Italy; (C.M.); (P.d.F.)
- Department of Biomedicina e Prevenzione, Tor Vergata University, 00133 Rome, Italy
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Poojary R, Song AF, Song BS, Song CS, Wang L, Song J. Investigating chimeric antigen receptor T cell therapy and the potential for cancer immunotherapy (Review). Mol Clin Oncol 2023; 19:95. [PMID: 37920415 PMCID: PMC10619195 DOI: 10.3892/mco.2023.2691] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 09/15/2023] [Indexed: 11/04/2023] Open
Abstract
Immunotherapy has emerged as a crucial treatment option, particularly for types of cancer that display resistance to conventional therapies. A remarkable breakthrough in this field is the development of chimeric antigen receptor (CAR) T cell therapy. CAR T cells are generated by engineering the T cells of a patient to express receptors that can recognize specific tumor antigens. This groundbreaking approach has demonstrated impressive outcomes in hematologic malignancies, including diffuse large B cell lymphoma, B cell acute lymphoblastic leukemia and multiple myeloma. Despite these significant successes, CAR T cell therapy has encountered challenges in its application against solid tumors, leading to limited success in these cases. Consequently, researchers are actively exploring novel strategies to enhance the efficacy of CAR T cells. The focus lies on augmenting CAR T cell trafficking to tumors while preventing the development of CAR T cell exhaustion and dysfunction. The present review aimed to provide a comprehensive analysis of the achievements and limitations of CAR T cell therapy in the context of cancer treatment. By understanding both the successes and hurdles, further advancements in this promising area of research can be developed. Overall, immunotherapy, particularly CAR T cell therapy, has opened up novel possibilities for cancer treatment, offering hope to patients with previously untreatable malignancies. However, to fully realize its potential, ongoing research and innovative strategies are essential in overcoming the challenges posed by solid tumors and maximizing CAR T cell efficacy in clinical settings.
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Affiliation(s)
- Rayansh Poojary
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807-3260, USA
| | - Andy Fang Song
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807-3260, USA
| | - Benny Shone Song
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807-3260, USA
| | - Carly Shaw Song
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807-3260, USA
| | - Liqing Wang
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807-3260, USA
| | - Jianxun Song
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807-3260, USA
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Mannan A, Kakkar C, Dhiman S, Singh TG. Advancing the frontiers of adaptive cell therapy: A transformative mechanistic journey from preclinical to clinical settings. Int Immunopharmacol 2023; 125:111095. [PMID: 37875038 DOI: 10.1016/j.intimp.2023.111095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/08/2023] [Accepted: 10/17/2023] [Indexed: 10/26/2023]
Abstract
Although the concept of using the patient's immune system to combat cancer has been around for a while, it is only in recent times that substantial progress has been achieved in this field. Over the last ten years, there has been a significant advancement in the treatment of cancer through immune checkpoint blockade. This treatment has been approved for multiple types of tumors. Another approach to modifying the immune system to detect tumor cells and fight them off is adaptive cell therapy (ACT). This therapy involves using T cells that have been modified with either T cell receptors (TCR) or chimeric antigen receptors (CAR) to target the tumor cells. ACT has demonstrated encouraging outcomes in different types of tumors, and clinical trials are currently underway worldwide to enhance this form of treatment. This review focuses on the advancements that have been made in ACT from preclinical to clinical settings till now.
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Affiliation(s)
- Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Chirag Kakkar
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Sonia Dhiman
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
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Nakazawa T, Maeoka R, Morimoto T, Matsuda R, Nakamura M, Nishimura F, Yamada S, Nakagawa I, Park YS, Ito T, Nakase H, Tsujimura T. An efficient feeder-free and chemically-defined expansion strategy for highly purified natural killer cells derived from human cord blood. Regen Ther 2023; 24:32-42. [PMID: 37303464 PMCID: PMC10247952 DOI: 10.1016/j.reth.2023.05.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/24/2023] [Accepted: 05/23/2023] [Indexed: 06/13/2023] Open
Abstract
Introduction Natural killer cells (NKCs) are immune cells that can attack cancer cells through the direct recognition of ligands without prior sensitization. Cord blood-derived NKCs (CBNKCs) represent a promising tool for allogenic NKC-based cancer immunotherapy. Efficient NKC expansion and decreased T cell inclusion are crucial for the success of allogeneic NKC-based immunotherapy without inducing graft-versus-host reactions. We previously established an efficient ex vivo expansion system consisting of highly purified-NKCs derived from human peripheral blood. Herein, we evaluated the performance of the NKC expansion system using CB and characterized the expanded populations. Methods Frozen CB mononuclear cells (CBMCs), with T cells removed, were cultured with recombinant human interleukin (rhIL)-18 and rhIL-2 under conditions where anti-NKp46 and anti-CD16 antibodies were immobilized. Following 7, 14, and 21 days of expansion, the purity, fold-expansion rates of NKCs, and the expression levels of NK activating and inhibitory receptors were assessed. The ability of these NKCs to inhibit the growth of T98G, a glioblastoma (GBM) cell line sensitive to NK activity, was also examined. Results All expanded T cell-depleted CBMCs were included in over 80%, 98%, and 99% of CD3-CD56+ NKCs at 7, 14, and 21 days of expansion, respectively. The NK activating receptors LFA-1, NKG2D, DNAM-1, NKp30, NKp44, NKp46, FcγRIII and NK inhibitory receptors TIM-3, TIGIT, TACTILE, NKG2A were expressed on the expanded-CBNKCs. Two out of three of the expanded-CBNKCs weakly expressed PD-1, yet gradually expressed PD-1 according to expansion period. One of the three expanded CBNKCs almost lacked PD-1 expression during the expansion period. LAG-3 expression was variable among donors, and no consistent changes were identified during the expansion period. All of the expanded CBNKCs elicited distinct cytotoxicity-mediated growth inhibition on T98G cells. The level of cytotoxicity was gradually decreased based on the prolonged expansion period. Conclusions Our established feeder-free expansion system yielded large scale highly purified and cytotoxic NKCs derived from human CB. The system provides a stable supply of clinical grade off-the-shelf NKCs and may be feasible for allogeneic NKC-based immunotherapy for cancers, including GBM.
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Affiliation(s)
- Tsutomu Nakazawa
- Grandsoul Research Institute for Immunology, Inc., Uda, Nara, 633-2221, Japan
- Clinic Grandsoul Nara, Matsui 8-1, Uda, Nara, 633-2221, Japan
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, 634-8522, Japan
| | - Ryosuke Maeoka
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, 634-8522, Japan
| | - Takayuki Morimoto
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, 634-8522, Japan
| | - Ryosuke Matsuda
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, 634-8522, Japan
| | - Mitsutoshi Nakamura
- Clinic Grandsoul Nara, Matsui 8-1, Uda, Nara, 633-2221, Japan
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, 634-8522, Japan
| | - Fumihiko Nishimura
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, 634-8522, Japan
| | - Shuichi Yamada
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, 634-8522, Japan
| | - Ichiro Nakagawa
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, 634-8522, Japan
| | - Young-Soo Park
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, 634-8522, Japan
| | - Toshihiro Ito
- Department of Immunology, Nara Medical University, Kashihara, Nara, 634-8522, Japan
| | - Hiroyuki Nakase
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, 634-8522, Japan
| | - Takahiro Tsujimura
- Grandsoul Research Institute for Immunology, Inc., Uda, Nara, 633-2221, Japan
- Clinic Grandsoul Nara, Matsui 8-1, Uda, Nara, 633-2221, Japan
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Giordano Attianese GMP, Ash S, Irving M. Coengineering specificity, safety, and function into T cells for cancer immunotherapy. Immunol Rev 2023; 320:166-198. [PMID: 37548063 DOI: 10.1111/imr.13252] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 07/03/2023] [Indexed: 08/08/2023]
Abstract
Adoptive T-cell transfer (ACT) therapies, including of tumor infiltrating lymphocytes (TILs) and T cells gene-modified to express either a T cell receptor (TCR) or a chimeric antigen receptor (CAR), have demonstrated clinical efficacy for a proportion of patients and cancer-types. The field of ACT has been driven forward by the clinical success of CD19-CAR therapy against various advanced B-cell malignancies, including curative responses for some leukemia patients. However, relapse remains problematic, in particular for lymphoma. Moreover, for a variety of reasons, relative limited efficacy has been demonstrated for ACT of non-hematological solid tumors. Indeed, in addition to pre-infusion challenges including lymphocyte collection and manufacturing, ACT failure can be attributed to several biological processes post-transfer including, (i) inefficient tumor trafficking, infiltration, expansion and retention, (ii) chronic antigen exposure coupled with insufficient costimulation resulting in T-cell exhaustion, (iii) a range of barriers in the tumor microenvironment (TME) mediated by both tumor cells and suppressive immune infiltrate, (iv) tumor antigen heterogeneity and loss, or down-regulation of antigen presentation machinery, (v) gain of tumor intrinsic mechanisms of resistance such as to apoptosis, and (vi) various forms of toxicity and other adverse events in patients. Affinity-optimized TCRs can improve T-cell function and innovative CAR designs as well as gene-modification strategies can be used to coengineer specificity, safety, and function into T cells. Coengineering strategies can be designed not only to directly support the transferred T cells, but also to block suppressive barriers in the TME and harness endogenous innate and adaptive immunity. Here, we review a selection of the remarkable T-cell coengineering strategies, including of tools, receptors, and gene-cargo, that have been developed in recent years to augment tumor control by ACT, more and more of which are advancing to the clinic.
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Affiliation(s)
- Greta Maria Paola Giordano Attianese
- Department of Oncology, Ludwig Institute for Cancer Research Lausanne, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Sarah Ash
- Department of Oncology, Ludwig Institute for Cancer Research Lausanne, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Melita Irving
- Department of Oncology, Ludwig Institute for Cancer Research Lausanne, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Callahan C, Haas L, Smith L. CAR-T cells for pediatric malignancies: Past, present, future and nursing implications. Asia Pac J Oncol Nurs 2023; 10:100281. [PMID: 38023730 PMCID: PMC10661550 DOI: 10.1016/j.apjon.2023.100281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 07/30/2023] [Indexed: 12/01/2023] Open
Abstract
The treatment landscape for pediatric cancers over the last 11 years has undergone a dramatic change, especially with relapsed and refractory B-cell acute lymphoblastic leukemia (ALL), due to the introduction of chimeric antigen receptor-T (CAR-T) cell therapy. Because of the success of CAR-T cell therapy in patients with relapsed and refractory B-cell ALL, this promising therapy is undergoing trials in multiple other pediatric malignancies. This article will focus on the introduction of CAR-T cell therapy in pediatric B-cell ALL and discuss past and current trials. We will also discuss trials for CAR-T cell therapy in other pediatric malignancies. This information was gathered through a comprehensive literature review along with using first hand institutional experience. Due to the potential severe toxicities related to CAR-T cell therapy, safe practices and monitoring are key. These authors demonstrate that nurses have a profound responsibility in preparing and caring for patients and families, monitoring and managing side effects in these patients, ensuring that study guidelines are followed, and providing continuity for patients, families, and referring providers. Education of nurses is crucial for improved patient outcomes.
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Affiliation(s)
- Colleen Callahan
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA
| | - Lauren Haas
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA
| | - Laura Smith
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA
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Balendran S, Tam C, Ku M. T-Cell Engaging Antibodies in Diffuse Large B Cell Lymphoma-An Update. J Clin Med 2023; 12:6737. [PMID: 37959202 PMCID: PMC10647650 DOI: 10.3390/jcm12216737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 10/12/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Novel cellular immunotherapies such as T-cell engaging antibodies (TCEAbs) are changing the landscape of treatment for diffuse large B cell lymphoma (DLBCL), especially in the relapsed/refractory (R/R) setting. TCEAbs harness the power of the host immune system to induce killing of tumor cells by binding to both the tumor antigen and the T-cell receptor. Since the approval of blinatumomab for R/R acute lymphoblastic leukemia, there has been significant development in novel TCEAbs. Many of these novel TCEAbs have shown promising effectiveness in R/R DLBCL, with favorable response rates including complete remissions, even in heavily pretreated patients. There are unique therapy-related toxicities with TCEAbs, namely cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), and it is important to both recognize and manage these side effects appropriately. This review examines the development and mechanism of action of these TCEAbs, and the available published data from clinical trials. Their role in the treatment of DLBCL, the management of therapy-related adverse events, and the mechanisms of resistance will also be discussed.
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Affiliation(s)
| | | | - Matthew Ku
- St. Vincent’s Hospital, Melbourne, Fitzroy, VIC 3065, Australia
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Ishihara M, Miwa H, Fujiwara H, Akahori Y, Kato T, Tanaka Y, Tawara I, Shiku H. αβ-T cell receptor transduction gives superior mitochondrial function to γδ-T cells with promising persistence. iScience 2023; 26:107802. [PMID: 37720098 PMCID: PMC10502403 DOI: 10.1016/j.isci.2023.107802] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 07/25/2023] [Accepted: 08/29/2023] [Indexed: 09/19/2023] Open
Abstract
Adoptive cell therapy using allogeneic γδ-T cells is a promising option for off-the-shelf T cell products with a low risk of graft-versus-host disease (GVHD). Long-term persistence may boost the clinical development of γδ-T cell products. In this study, we found that genetically modified Vγ9+Vδ2+ T cells expressing a tumor antigen-specific αβ-TCR and CD8 coreceptor (GMC) showed target-specific killing and excellent persistence. To determine the mechanisms underlying these promising effects, we investigated metabolic characteristics. Cytokine secretion by γδ-TCR-stimulated nongene-modified γδ-T cells (NGMCs) and αβ-TCR-stimulated GMCs was equally suppressed by a glycolysis inhibitor, although the cytokine secretion of αβ-TCR-stimulated GMCs was more strongly inhibited by ATP synthase inhibitors than that of γδ-TCR-stimulated NGMCs. Metabolomic and transcriptomic analyses, flow cytometry analysis using mitochondria-labeling dyes and extracellular flux analysis consistently suggest that αβ-TCR-transduced γδ-T cells acquire superior mitochondrial function. In conclusion, αβ-TCR-transduced γδ-T cells acquire superior mitochondrial function with promising persistence.
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Affiliation(s)
- Mikiya Ishihara
- Department of Medical Oncology, Mie University Hospital, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Hiroshi Miwa
- Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
| | - Hiroshi Fujiwara
- Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
| | - Yasushi Akahori
- Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
| | - Takuma Kato
- Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Yoshimasa Tanaka
- Center for Medical Innovation, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan
| | - Isao Tawara
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Hiroshi Shiku
- Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
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Ibáñez-Navarro M, Fernández A, Escudero A, Esteso G, Campos-Silva C, Navarro-Aguadero MÁ, Leivas A, Caracuel BR, Rodríguez-Antolín C, Ortiz A, Navarro-Zapata A, Mestre-Durán C, Izquierdo M, Balaguer-Pérez M, Ferreras C, Martínez-López J, Valés-Gómez M, Pérez-Martínez A, Fernández L. NKG2D-CAR memory T cells target pediatric T-cell acute lymphoblastic leukemia in vitro and in vivo but fail to eliminate leukemia initiating cells. Front Immunol 2023; 14:1187665. [PMID: 37928520 PMCID: PMC10622787 DOI: 10.3389/fimmu.2023.1187665] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 10/02/2023] [Indexed: 11/07/2023] Open
Abstract
Introduction Refractory/relapsed pediatric acute leukemia are still clinically challenging and new therapeutic strategies are needed. Interactions between Natural Killer Group 2D (NKG2D) receptor, expressed in cytotoxic immune cells, and its ligands (NKG2DL), which are upregulated in leukemic blasts, are important for anti-leukemia immunosurveillance. Nevertheless, leukemia cells may develop immunoescape strategies as NKG2DL shedding and/or downregulation. Methods In this report, we analyzed the anti-leukemia activity of NKG2D chimeric antigen receptor (CAR) redirected memory (CD45RA-) T cells in vitro and in a murine model of T-cell acute lymphoblastic leukemia (T-ALL). We also explored in vitro how soluble NKG2DL (sNKG2DL) affected NKG2D-CAR T cells' cytotoxicity and the impact of NKG2D-CAR T cells on Jurkat cells gene expression and in vivo functionality. Results In vitro, we found NKG2D-CAR T cells targeted leukemia cells and showed resistance to the immunosuppressive effects exerted by sNKG2DL. In vivo, NKG2D-CAR T cells controlled T cell leukemia burden and increased survival of the treated mice but failed to cure the animals. After CAR T cell treatment, Jurkat cells upregulated genes related to proliferation, survival and stemness, and in vivo, they exhibited functional properties of leukemia initiating cells. Discussion The data here presented suggest, that, in combination with other therapeutic approaches, NKG2D-CAR T cells could be a novel treatment for pediatric T-ALL.
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Affiliation(s)
- Marta Ibáñez-Navarro
- Hematological Malignancies-H12O Lab. Clinical Research Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Adrián Fernández
- Hematological Malignancies-H12O Lab. Clinical Research Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Adela Escudero
- Pediatric Oncology Department, Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, Madrid, Spain
| | - Gloria Esteso
- Tumor Immune Activation and Evasion Lab. Immunology and Oncology Department, National Biotechnology Center (CNB), Madrid, Spain
| | - Carmen Campos-Silva
- Tumor Immune Activation and Evasion Lab. Immunology and Oncology Department, National Biotechnology Center (CNB), Madrid, Spain
| | - Miguel Ángel Navarro-Aguadero
- Hematological Malignancies-H12O Lab. Clinical Research Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Alejandra Leivas
- Hematological Malignancies-H12O Lab. Clinical Research Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Beatriz Ruz Caracuel
- Pediatric Oncology Department, Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, Madrid, Spain
| | - Carlos Rodríguez-Antolín
- Biomarkers and Experimental Therapeutics in Cancer, Hospital La Paz Institute for Health Research-IdiPAZ, Madrid, Spain
- Cancer Epigenetics Laboratory, Genetic Unit, Hospital Universitario La Paz, Madrid, Spain
| | - Alejandra Ortiz
- Hematological Malignancies-H12O Lab. Clinical Research Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Alfonso Navarro-Zapata
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
| | - Carmen Mestre-Durán
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
| | - Manuel Izquierdo
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain
| | - María Balaguer-Pérez
- Hematological Malignancies-H12O Lab. Clinical Research Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Cristina Ferreras
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
| | - Joaquín Martínez-López
- Hematological Malignancies-H12O Lab. Clinical Research Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Mar Valés-Gómez
- Tumor Immune Activation and Evasion Lab. Immunology and Oncology Department, National Biotechnology Center (CNB), Madrid, Spain
| | - Antonio Pérez-Martínez
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
- Pediatric Hemato-Oncology, Hospital Universitario La Paz, Madrid, Spain
- Pediatric Department, Universidad Autónoma de Madrid, Madrid, Spain
| | - Lucía Fernández
- Hematological Malignancies-H12O Lab. Clinical Research Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
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